Compounds with (1 E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof

ABSTRACT

The present invention includes compounds, pharmaceuticals and cosmetics having at least one (substituted phenyl)-propenal moiety. The compounds and compositions of the present invention are useful in the treatment or prevention of medical conditions including androgen associated conditions, androgen associated inflammation, a wound (the compounds assist with wound healing), acne, rheumatoid arthritis, psoriasis, rosacea, and alopecia; Kennedy&#39;s disease (spinal and bulbar muscular atrophy, or SBMA), polyglutamine-mediated motor neuron degeneration; cancers such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular (liver) cancer, and pancreatic cancer; and other medical conditions described herein. Treatment of such medical conditions includes administering to an individual suffering from a medical condition describe herein, a therapeutically effective amount of any of the disclosed compounds, their derivatives, or pharmaceutical compositions thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation-in-Part of U.S. patentapplication Ser. No. 12/800,251, filed May 11, 2010, now U.S. Pat. No.8,202,905, entitled “Compounds with (Substituted Phenyl)-PropenalMoiety, Their Derivatives, Biological Activity, and Use Thereof;” whichis a Divisional application of U.S. patent application Ser. No.12/008,124, filed Jan. 8, 2008, now U.S. Pat. No. 8,236,852, entitled“Compounds with (Substituted Phenyl)-Propenal Moiety, Their Derivatives,Biological Activity, and Use Thereof;” which claims benefit of priorityto United Sates patent application Ser. No. 60/879,458 filed on Jan. 8,2007, entitled “Compounds with (Substituted Phenyl)-Propenal Moiety,Their Derivatives, Biological Activity, and Use Thereof;” each of whichis herein incorporated by reference in its entirety. The presentapplication is also a Continuation-in-Part of U.S. patent applicationSer. No. 12/008,124, filed Jan. 8, 2008, now U.S. Pat. No. 8,236,852,entitled “Compounds with (Substituted Phenyl)-Propenal Moiety, TheirDerivatives, Biological Activity, and Use Thereof;” which claims benefitof priority to United Sates patent application Ser. No. 60/879,458 filedon Jan. 8, 2007, entitled “Compounds with (Substituted Phenyl)-PropenalMoiety, Their Derivatives, Biological Activity, and Use Thereof;” eachof which is herein incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to compounds with biological activity andpharmaceutical and cosmetic formulations thereof, their derivatives andmethods of use, more specifically the present invention includescompounds with at least one (substituted phenyl)-propenal moiety andtheir biological activity and use thereof. The present invention alsorelates to compounds with(1E,6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dionestructural scaffold and their biological activity and uses thereof.

BACKGROUND OF THE INVENTION

It is well known that certain natural products may possess therapeuticeffects, which has lead to their use in the treatment and prevention ofhuman diseases across many cultures (e.g., Chinese herbal medicines andmany other folk medicines). The effectiveness of such treatments haslead the pharmaceutical industry to seek and isolate active compoundsfrom these natural products and develop the active ingredients astherapeutic or prophylactic drugs for the treatment and prevention of avariety of diseases or medical conditions. Thus many commonly usedpharmaceuticals have been developed or have arisen from naturalproducts. Among these include, aspirin (acetylsalicylic acid), which wasisolated from bark of the willow tree; ephedrine and pseudoephedrine,which were isolated from a Chinese herb Má Huang; and penicillin, whichwas isolated from fungus (Pennicillium chrysogenum). However, compoundsisolated from natural products are known to play certain physiologicalfunction(s) in its native host; whereas their therapeutic effectsagainst human diseases are not readily apparent. Historically, suchtherapeutic treatments were derived merely by accumulated experiences or“trial and error” in humans. Moreover, because such compounds were notinitially created for use in humans, the compounds in their native formare frequently not in the most optimal form, both in structure as wellas efficacy, to treat human diseases. However, today's modern chemistrytechnology, including analytical and synthetic chemistries, togetherwith the advances in medicinal biology have made it possible for one todissect a chemical structure and localize a “pharmacophore” (a corestructure that is essential for the therapeutic activity) within acompound such as one isolated from a natural product; furthermore, thesenew techniques allow one to synthesize new compounds, based on thestructure of a pharmacophore, that possess optimal or even bettertherapeutic efficacy.

In this invention we have demonstrated that a compound with a single(4-hydroxy-3-methoxy-phenyl)-propenal moiety possesses an activity thatcould reduce the expression of androgen receptor (AR) protein byenhancing its degradation. This discovery resulted in part from ourextensive study of compound ASC-J9(1,7-Bis-(3,4-dimethoxy-phenyl)-5-hydroxy-hepta-1,4,6-trien-3-one), adimethylated form of a natural compound curcumin (existing as a majorpigment in a turmeric plant). Compound curcumin and many of its analogshave been reported to possess numerous biological activities in vitro,such as, anti-oxidant, anti-inflammatory, anti-tumor, andantiangiogenesis activities; but neither curcumin nor its analogues havebeen developed into a therapeutic drug to treat human diseases. Thisindicates curcumin in its native form is probably not an optimalmolecule for development into a therapeutic drug.

Previously we have discovered compounds ASC-J9 and ASC-J15(5-Hydroxy-7-(4-hydroxy-3-methoxy-phenyl)-4-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-hepta-4,6-dienoicacid ethyl ester) (FIG. 1), both possess potent prostate cancerinhibitory and anti-androgenic activity. These two compounds, in ourhand, also exhibited more potent anti-prostate cancer activity than acurrent therapeutic drug hydroxyl flutamide (HF), a class of“non-steroid anti-androgen” drug that is widely used to treat humanprostate cancer.

After extensive further study of the structure and bioactivity of ASC-J9and ASC-J15, we were surprised to find that the (substitutedphenyl)-propenal moieties shared by these two compounds are actually thecore structure(s) that attribute to the potent anti-androgen and anti-ARactivity of these compounds but not the entire curcumin-like structure.Based in part on this finding we have generated, by chemicallysynthesis, numerous new compounds, including compounds that possess one,two, three or four (substituted phenyl)-propenal moieties to furthersupport the concept that a (substituted phenyl)-propenal moiety is thepharmacophore of these compounds. Results from our study are able toshow that the increase in number of these moieties within a compoundstructure may alter or may increase the anti-androgen and anti-ARactivity of the compound. We also demonstrate herein thatanti-androgenic activity is present within compounds having a single(substituted phenyl)-propenal moiety. New derivatives, based on our newcompounds with at least one (substituted phenyl)-propenal moiety, werealso synthesized by the present inventors to elucidate not only thepharmacophore structure but also to evaluate the anti-androgenic andanti-cancer activities. The new compounds, provided herein by theinventors further show significant improvements and optimization ofbioactivity, bioavailability, water solubility and other criteriaessential for the development of therapeutic drug.

SUMMARY

The present invention provides biologically active compounds having atleast one (substituted phenyl)-propenal moiety. Thus it is an object ofthe present invention to provide compounds having at least one(substituted phenyl)-propenal moiety for use as a treatment for amedical condition, such as a human medical condition.

In one aspect of the present invention a compound having at least one(substituted phenyl)-propenal moiety is provided, the compound havingthe formula according to formula I:

wherein 1) R₃ and R₄ are each independently selected from the groupconsisting of alkoxy, hydroxy, and hydrogen; and 2) X is selected fromthe group consisting of hydroxy, alkoxy, ethyl propionate, ethyl methylcarbonate, and carbonyl alkyl. In some embodiments the compound hasformula selected from the group consisting of monomers 1, 3, 5, 6 and 7.These monomers are provided below:

Monomers:

In another aspect of the present invention a compound is providedincluding a (substituted phenyl)-propenal moiety having the formulaaccording to (IIa) or (IIb):

wherein: 1) R₃, R₄, R₃′, and R₄′ are independently selected from thegroup consisting of —H, —OH, and —OCH₃; 2) L is a C0-C8 alkylene or L isan unsaturated alkenylene or alkynl when Z is nothing; 3) Z is selectedfrom the group consisting of —H, —OH, an aromatic ring, a cycloalkyl,—COR₁, —CO₂R₁, —CONR₁R₂, —NR₁R₂, —CX₃, wherein R₁ and R₂ areindependently selected from the group consisting of —H, —CH₃, and —C₂H₅;and 4) X is a halogen atom selected from the group consisting of —F,—Cl, and —Br. The formula IIa and IIb are the equilibrate tautomers as acommon phenomenon of diketone (see, for example, FIG. 9). In someembodiments the compound is selected from the group consisting of II-1,II-2, II-3, II-4 and II-5. The formulas provided as:

In another aspect of the present invention, a compound is providedaccording to formula IIc:

wherein 1) R₃, R₄, R₃′, and R₄′ are independently selected from thegroup consisting of —H, —OH, and —OCH₃; and 2) R₁, and R₂ areindependently selected from the group consisting of —H, —CH₃, —C₂H₅, asubstituted aryl and a substituted benzyl group.

In another aspect of the present invention, a compound is providedaccording to formula III:

wherein R₃, R₄, R₃′, R₄′, R₃″, and R₄″ are each independently selectedfrom the group consisting of alkoxy, hydroxy, and hydrogen. In someembodiments, the compound includes the formula III-1 or III-2, which isprovided as:

In another aspect of the present invention, a compound is providedaccording to the formula IV:

wherein R₃, R₄, R_(3′), R_(4′), R_(3″), R_(4″), R_(3′″) and R_(4′″) areeach independently selected from the group consisting of alkoxy,hydroxy, and hydrogen. In some embodiments the compound includes theformula IV-1:

In another aspect of the present invention a compound is providedaccording to formula V:

wherein 1) each “n” is independently 1, 2, or 3; 2) R₃, R₄, R₃′, and R₄′are independently selected from the group consisting of —H, —OH, and—OCH₃; 3) L-Z side chain can be no-exist, but if L-Z side chain exists,L is a C0-C8 alkylene, or an unsaturated alkenylene or alkynl when Z isnothing; 4) Z is selected from the group consisting of —H, —OH, anaromatic ring, a cycloalkyl, —COR₁, —CO₂R₁, —CONR₁R₂, —NR₁R₂, —CX₃; 5)R₁ and R₂ are independently selected from the group consisting of —H,—CH₃, and —C₂H₅; and 6) X is a halogen atom selected from the groupconsisting of —F, —Cl, and —Br. In some embodiments the compound isprovided according to formula V-1 or V-2:

The present invention also provides biologically active compounds havinga structure scaffold of 4,4-disubstituted1,7-bis-(3,4-dimethoxyphenyl)-hepta-1,6-diene-3,5-dione. Thus, it is anobject of the present invention to provide compounds having two propersubstations at C4 position of1,7-bis-(3,4-dimethoxyphenyl)-hepta-1,6-diene-3,5-dione structure foruse as a treatment for a medical conditions, such as but not limited to,human medical conditions.

In one aspect of the present invention a compound having a4,4-disubstituted1,7-bis-(3,4-dimethoxyphenyl)-hepta-1,6-diene-3,5-dione structuralscaffold is provided, the compound having the formula according toformula VI:

wherein L is a carbonyl, alkylene, alkenylene, or alkynl when Z is notpresent;Z is —H, —OH, a substituted styrenyl, an aromatic ring, a cycloalkyl,—COR₁, —CONR₁R₂, or —CX₃, wherein R₁ and R₂ are each —H, —CH₃, or—C_(n)H_(2n+1), (n=2-4), or a heterocyclic, or a heteroaryl moiety, orR₁ and R₂ together to form a heterocyclic ring, such as a morphorine;X is —F, —Cl, or —Br;Y is H when L is an alkylene, such as —CH₂, and Z is —CONR₁R₂, R₁ and R₂are each —H and a heterocyclic or a heteroaryl, or a cycloalkyl, such asa cyclopentanyl; or Y is a short alkyl(C1-3), such as a methyl (—CH₃),or —F, Cl, Br.

In another aspect of the present invention, the compound is selectedfrom the group consisting of C4-R₁R₂. The formulas provided as:

The R₁ and R₂ represent a series of function groups as listed in theFIG. 10.

In another aspect of the present invention a pharmaceutical formulationor cosmetic formulation is disclosed including a compound including atleast one (substituted phenyl)-propenal moiety as provided in thepresent application and having a desired biological activity. Thepharmaceutical formulation or cosmetic formulation may provide acompound of the present invention and a pharmaceutically acceptablecarrier or a cosmetically acceptable carrier. In various nonlimitingembodiments, the compound may include monomer 1, 3, 5, 6 or 7 alone orin combination. In further embodiments, the compound includes theformula according to formulas I, II, III, IV, V, or a combinationthereof. Thus the compound may include at least one, two, three, four,five or more (substituted phenyl)-propenal moieties.

In another aspect of the present invention, a pharmaceutical formulationor cosmetic formulation is disclosed including a compound with astructure of 4,4-disubstituted1,7-bis-(3,4-dimethoxyphenyl)-hepta-1,6-diene-3,5-diode as provided inthe present application and having a desired biological activity. Thepharmaceutical formulation or cosmetic formulation can provide acompound of the present invention and a pharmaceutically acceptablecarrier or a cosmetically acceptable carrier. In various non-limitingexamples, the compound includes the formula according to formula VI orformula VII, or a combination thereof.

In another aspect of the present invention a method of treating amedical condition is disclosed including administering a compoundincluding at least one (substituted phenyl)-propenal moiety having adesired or suspected of having a desired biological activity to anindividual in need thereof. The compound may be any disclosed hereinalone or in combination. The compounds of the present invention may beused to treat, prevent or ameliorate symptoms from androgen associateddisorders. Non-limiting examples of medical conditions that may betreated with the disclosed compounds are androgen associatedinflammation including a wound (the compounds assist with woundhealing), acne, rheumatoid arthritis, psoriasis, rosacea, and alopecia;Kennedy's disease (spinal and bulbar muscular atrophy, or SBMA),polyglutamine-mediated motor neuron degeneration; cancers such asprostate cancer, bladder cancer, breast cancer, ovarian cancer,hepatocellular (liver) cancer, and pancreatic cancer; and other medicalconditions described herein. Treatment of such medical conditionsincludes administering to an individual suffering from a medicalcondition describe herein, a therapeutically effective amount of any ofthe disclosed compounds, their derivatives, or pharmaceuticalcompositions thereof.

In another aspect of the present invention, a method of treating amedical condition is disclosed including administering a compoundincluding 4,4-disubstituted1,7-bis-(3,4-dimethoxyphenyl)-hepta-1,6-diene-3,5-dione structuralscaffold having a desired biological activity to an individual in needthereof. The compound may be any disclosed herein alone or incombination. The compounds of the present invention may be used totreat, prevent or ameliorate symptoms from androgen and androgenreceptor (AR) associated disorders, Non-limiting examples of medicalconditions that can be treated with the disclosed compounds are androgenassociated inflammation including a wound (the compounds assist withwound healing), acne, rheumatoid arthritis, psoriasis, rosacea, andalopecia; Kennedy's Disease, (spinal and bulbar muscular atrophy, orSBMA), polyglutamine-mediated motor neuron degeneration; cancers such asprostate cancer, bladder cancer, breast cancer, ovarian cancer,hepatocellular (liver) cancer, and pancreatic cancer; and other medicalconditions described herein. Treatment of such medical conditionsincludes administering to an individual suffering from a medicalcondition, including but not limited to describe herein, atherapeutically effective amount of any of the disclosed compounds,their derivatives, or pharmaceutical compositions thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a structural representation of compounds ASC-J9(1,7-Bis-(3,4-dimethoxy-phenyl)-5-hydroxy-hepta-1,4,6-trien-3-one) andASC-J15(5-Hydroxy-7-(4-hydroxy-3-methoxy-phenyl)-4-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-hepta-4,6-dienoicacid ethyl ester), which were previously shown to have anti-androgenicactivities.

FIG. 2A, FIG. 2B, FIG. 2C, FIG. 2D, FIG. 2E, and FIG. 2F. depict a tableincluding a nonlimiting listing of newly synthesized compoundsencompassed by the present invention including at least one (substitutedphenyl)-propenal moiety, with their structures, chemical formulas andmolecular weights.

FIG. 3 depicts a table of Western Blot densitometric data showingcompounds having different number of(4-hydroxy-3-methoxy-phenyl)-propenal moieties are capable of reducingAndrogen Receptor (AR) expression in human prostate cancer CWR22Rv1cells.

FIG. 4 depicts Western Blot images showing newly provided compounds withat least one (4-hydroxy-3-methoxy-phenyl)-propenal moiety are capable ofreducing Androgen Receptor (AR) protein expression in human prostatecancer CWR22Rv1 cells.

FIG. 5 depicts a table showing some selected ASC compounds and monomersare capable of inhibiting proliferation of human prostate cancer cells(LNCaP and CWR22Rv1) stimulated by DHT in vitro.

FIG. 6 depicts Western Blot data showing four compounds ASC-Q49,ASC-Q103, ASC-JM12, and ASC-JM4, at various concentrations, are capableof reducing endogenous AR expression in LNCaP and CWR22Rv1 humanprostate cancer cells.

FIG. 7 depicts Western Blot data showing compounds ASC-J9 and ASC-JM5enhances AR protein degradation in the presence of a protein synthesisinhibitor, cycloheximide (CHX), tested in LNCaP cells.

FIG. 8 depicts two tables (8 a and 8 b) that summarize the potency ofrepresentative ASC compounds in reducing endogenous AR proteinexpression (using Western Blot analysis) at various concentrations, whentested in LNCaP and CWR22Rv1 human prostate cancer cells.

FIG. 9 depicts a structural representation of compounds ASC-JM17 andASC-Q49 as an equilibrium of enol-ketone and diketone tautomers whichhave anti-androgenic and anti-AR activities.

FIG. 10 depicts a table including a nonlimiting listing of compoundsencompassed by the present invention including 4,4-disubstituted1,7-bis-(3,4-dimethoxyphenyl)-hepta-1,6-diene-3,5-dione scaffold, withtheir structures, chemical formulas, and molecular weights.

FIG. 11A, FIG. 11B and FIG. 11C: depict UV spectra of ASC-Q49 diketonetautomer peak (FIG. 11A, RT 20.6 minutes), enol tautomer peak (FIG. 11B,RT 23.7 minutes), and compound 6 (FIG. 11C, RT 21.1 minutes) from HPLCanalysis.

DETAILED DESCRIPTION A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. All patents, applications,published applications and other publications referred to areincorporated by reference in their entirety, including disclosedstructures, formulas, methods of use, methods of treatment, and methodsof production. In the event that there is a plurality of definitions fora term herein, those in this section prevail unless stated otherwise.

The term “(substituted phenyl)-propenal moiety” as used herein refers toa composition including a phenyl group having attached thereto apropenal moiety (when m equals 1) and an alkoxy or hydroxy moiety, or analkyl or substituted alkyl moiety. The substitutions may be positionedmeta or para or ortho with respect to the propenal moiety as used hereinand refers to a general formula

Where n may be any number of 1, 2, 3 or 4; and m may be any number of 1,2, 3, 4, or more.

The term “alkyl” as used herein refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing no unsaturation, having from one to ten carbon atoms,and which is attached to the rest of the molecule by a single bond, e.g.methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl(t-butyl), and the like.

The term “alkenyl” as used herein refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing at least one double bond, having from two to tencarbon atoms, and which is attached to the rest of the molecule by asingle bond or a double bond, e.g. ethenyl, prop-1-enyl, pent-1-enyl,penta-1,4-dienyl, and the like.

The term “alkenylene” as used herein refers to a straight or branchedhydrocarbon chain which contains a carbon-to-carbon double bond and isrepresented by the formula C_(n)H_(2n−2), wherein hydrogen may bereplaced by an additional carbon-to-carbon double bond or a monovalentsubstituent, e.g. ethenylene, prop-1-enylene and the like.

The term “alkoxy” as used herein refers to the radical having theformula —OR wherein R is an alkyl, haloalkyl or cycloalkyl. An“optionally substituted alkoxy” refers to the radical having the formula—OR wherein R is an optionally substituted alkyl as described herein.

The term “alkynl” as used herein refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing at least one triple bond, having from two to tencarbon atoms, and which is attached to the rest of the molecule by asingle bond or a triple bond, e.g. ethynyl, prop-1-ynyl, but-1-ynyl,pent-1-ynyl, pent-3-ynyl and the like.

The term “aryl” as used herein refers to a radical of carbocyclic ringsystem wherein at least one of the rings is aromatic. The aryl may befully aromatic or may contain an aromatic ring in combination with anon-aromatic ring. A “biaryl system” is a compound that includes atleast two aryl groups.

The term “cycloalkyl” as used herein refers to a stable monovalentmonocyclic or bicyclic hydrocarbon radical consisting solely of carbonand hydrogen atoms, having from three to ten carbon atoms, and which issaturated and attached to the rest of the molecule by a single bond,e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term “di-ketone bridge”, or “ketone-enol bridge” as used hereinrefers to a straight or branched hydrocarbon chain including two ketonesor an enol positioned in close proximity to a ketone respectively. The“di-ketone bridge” or “ketone-enol bridge” is positioned between atleast two aryl moieties.

The term “hydroxyalkyl” as used herein refers to a straight or branchedhydroxy substituted hydrocarbon chain radical having from one to tencarbon atoms, e.g. CH₂OH, —(CH₂)₂OH and the like.

The term “androgen” as used herein refers to androgen hormones such astestosterone and dihydrotestosterone (DHT). DHT is the converted productof testosterone by the 5-alpha-reductase enzyme. Androgen stimulates orcontrols the development and maintenance of masculine characteristicsand other physiological functions in vertebrates by binding to androgenreceptors, which in turn binds to the androgen/AR-controlled genes (DNA)and activates or modulates the gene.

The term “androgen receptor” as used herein or “AR” refers to theintracellular receptor that specifically binds androgens, includingtestosterone and DHT. AR includes all mammalian isoforms, splicevariants and polymorphisms of the androgen receptor.

The term “estrogen receptor” or “ER” or “ER family” as used hereinrefers to the intracellular receptor specific for estradiol (the mainendogenous estrogen). When bound to a hormone, it acts as atranscription factor (it regulates the reading of DNA and production ofproteins). ER includes ERα and ERβ. ER includes all mammalian isoforms,splice variants, and polymorphisms of the nuclear receptor.

The term “glucocorticoid receptor” or “GR” as used herein refers to theintracellular receptor that has a high affinity to cortisol and otherglucocorticoids. GR includes all mammalian isoforms, splice variants,and polymorphisms of the nuclear receptor.

The term “progesterone receptor” or “PR” as used herein refers to theintracellular steroid receptor that specifically binds progesterone. PRincludes all mammalian isoforms, splice variants and polymorphisms ofthe nuclear receptor.

The term “peroxisome proliferator activated receptor” or “PPAR” as usedherein refers to all isotypes of PPAR, including PPARα, PPARβ and PPARγ.PPAR increases transcription of target genes by binding to a specificnucleotide sequence in the gene's promoter. When bound to its fatty acidligand, PPARα forms a heterodimeric complex with the retinoid X receptor(R×R) to regulate transcription. PPARγ is activated by prostaglandinsand leukotrienes and regulates the gene expression of proteins involvedin the storage of fatty acids. PARβ is weakly activated by fatty acids,prostaglandins, and leukotrienes. Its physiological ligand has not beenidentified.

The term “retinoic acid receptor” or “RAR” as used herein refers to theintracellular receptor known to bind many retinoid forms. “RAR” includesall family members, which include RARα, RARβ and RARγ. “RAR” includesall mammalian isoforms, splice variants and polymorphisms of the nuclearreceptor.

The term “retinoid×receptor” or “R×R” as used herein refers to theintracellular receptor that specifically binds 9-cis-Retinoic acid,“R×R” includes all mammalian isoforms, splice variants and polymorphismsof the nuclear receptor.

The term “steroid receptor” or “steroid nuclear receptor” as used hereinrefers to intracellular receptors that bind to and regulate thetranscription of DNA under the regulation of steroid hormones. Receptorsfor the different hormones have strong structural and functionalsimilarities which point to an evolution from a common ancestral geneand therefore are considered a gene superfamily. Representativereceptors which belong to this gene superfamily include the DNA bindingand regulatory proteins controlled by the steroid hormones estradiol(ER), glucocorticoid (GR), androgen (AR), progesterone (PR),mineralocorticoid (MR), the nonsteroid hormones triiodothyronine (T3R)and dihydroxyvitamin D3 (VDR), and two classes of retinoid (all-transretinoic acid and 9-cis retinoic acid) receptors (RARs and RXRsrespectively). More than 32 genes encoding at least 75 proteins withdifferent DNA specificity, regulation, or hormone affinity have beenidentified as part of this gene superfamily. New members of thissuperfamily are being reported frequently and are herein intended to beincorporated by reference in their entirety as published in peerreviewed scientific literature or as provided in sequence databases suchas GenBank, whether DNA, RNA or polypeptide sequence, and SWISSPROT.Using new biotechnology, molecular biologists and biochemists haveidentified protein receptors for which the ligands have not yet beenidentified, thus giving birth to a class of “orphan receptors”. “Steroidreceptor” includes all mammalian splice variants and isoforms of thesteroid receptors.

The term “extended release” as used herein refers to dosage form thatprovides for the delayed, slowed over a period of time, continuous,discontinuous, or sustained release of a compound or composition.

The term “pharmaceutically acceptable” as used herein refers to approvedor approvable by a regulatory agency of the Federal or a stategovernment for use in animals, and more particularly in humans. The term“pharmaceutically acceptable carrier” refers to an approved orapprovable diluent, adjuvant, excipient or carrier with which a compoundis administered.

The term “prodrug” as used herein refers to a compound that, upon invivo administration, is metabolized by one or more steps or processes orotherwise converted to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, thepharmaceutically active compound is modified such that the activecompound will be regenerated by metabolic processes. The prodrug may bedesigned to alter the metabolic stability or the transportcharacteristics of a drug, to mask side effects or toxicity, to improvethe flavor of a drug or to alter other characteristics or properties ofa drug. In some but not all instances, the prodrug includes a cleavableester, which upon cleavage, releases the active form.

The term “therapeutically effective amount” refers to the amount of acompound that, when administered to a patient for treating a disease ordisorder, is sufficient to affect such treatment for the disease ordisorder. The “therapeutically effective amount” will vary depending onthe compound, the disease or disorder and its severity and the age andweight of the patient to be treated. The “therapeutically effectiveamount” may include a series of administrations that eventually causes adesired effect whether or not the initial administration is effective.

The term “derivative” as used herein refers to variations on a corestructure or pharmacophore that yields a desired effect. Derivatives mayinclude substitutions along the phenyl ring, the propenal region of themolecule or along a side chain. Thus derivatives encompassed hereininclude compounds formed from or include at least one disclosedcompound, such as those identified in formulas I, II, III, IV, or V. Itmay be desirable to form derivatives of the particular compounds tomodulate solubility, efficacy, aggregation and the like.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, Biochem. 1972 11:942-944).

B. Compounds and Compositions Including (Substituted Phenyl)-PropenalMoieties

The inventors of the present invention have found that compoundsdescribed herein, including those with at least one (substitutedphenyl)-propenal moiety show promise for the treatment or prevention ofmedical conditions. Moreover compounds disclosed herein are believed topossess activities, such as reducing the proliferation of cells that arebelieved to have or suspected of having a cancerous profile.Additionally, compounds disclosed herein demonstrate the ability toselectively modulate populations of steroid receptors. Thus it is anobject of the present invention to provide compounds having biologicalactivities useful in the treatment or prevention of disease in mammals,such as humans.

The present invention discloses and encompasses a variety of compoundsand their derivatives having utility in the areas of medical treatment,such as in the treatment or prevention of medical conditions. Thuscompositions disclosed herein may be provided or administered ascompounds themselves or may be adapted with a suitable carrier to effectthe desired treatment. When providing the compounds disclosed herein asa pharmaceutical, the compounds may be provided in combination with apharmaceutically acceptable carrier. When providing the compoundsdisclosed herein as a cosmetic, the compounds may be provided incombination with a cosmetically acceptable carrier. Pharmaceuticallyacceptable carriers and cosmetically acceptable carriers may be thesame, may be derived from one another and the like as known in thepharmaceutical and cosmetic industries, or may be different such as butnot limited to variations depending on desired route of administration.Compounds may be tested for solubility, activity and dipole momentbefore or after the preparation as a pharmaceutical or cosmetic and maybe tested alone or in combination with other compounds disclosed hereinfor synergistic effects. Thus the present invention includes one or morecompound and derivatives thereof, including those with hydrophilic orhydrophobic additions, substitutions or subtractions.

In one aspect of the present invention a compound having at least one(substituted phenyl)-propenal moiety is provided. In some embodiments,compounds having a (substituted phenyl)-propenal moiety have biologicalactivity including anti-androgen/anti-AR biological activity. In onespecific embodiment of the present invention the (substitutedphenyl)-propenal moiety has the formula according to formula I:

wherein 1) R₃ and R₄ are each independently selected from the groupconsisting of alkoxy, hydroxy, and hydrogen; and 2) X is selected fromthe group consisting of hydroxy, alkoxy, ethyl propionate, ethyl methylcarbonate, and carbonyl alkyl. As can be viewed in the Figures,compounds having at least one (substituted phenyl)-propenal moiety arecapable of decreasing the presence of the androgen receptor or inducingdegradation of the androgen receptor. Moreover compounds having at leastone (substituted phenyl)-propenal moiety were shown to reduce cancercell growth or proliferation of cancer cells. Such inhibition occurredin the presence of a compound capable of cancer cell stimulation. Invarious nonlimiting embodiments described herein the compound includes a(substituted phenyl)-propenal compound or a pharmaceutically acceptablesalt thereof, selected from monomer 1, 3, 5, 6 or 7, alone or incombination, the monomers being provided below:

Monomers:

In various embodiments, derivatives of the above referenced monomershaving biological activity are also provided. The derivatives may havesubstitutions at one or more positions to increase one or morecharacteristic such as activity, solubility and the like. Suchderivatives may modulate the dipole moment of a compound and may resultin a composition that is more or less hydrophobic or hydrophilic.

In another aspect of the present invention a compound is providedincluding a (substituted phenyl)-propenal moiety having the formulaaccording to (IIa) or (IIb):

wherein: 1) R₃, R₄, R₃′, and R₄′ are independently selected from thegroup consisting of —H, —OH, and —OCH₃; 2) L is a C0-C8 alkylene or L isan unsaturated alkenylene or alkynl when Z is nothing; 3) Z is selectedfrom the group consisting of —H, —OH, an aromatic ring, a cycloalkyl,—COR₁, —CO₂R₁, —CONR₁R₂, —NR₁R₂, —CX₃, wherein R₁ and R₂ areindependently selected from the group consisting of —H, —CH₃, and —C₂H₅;4) X is halogen atom selected from the group consisting of —F, —Cl, and—Br; and further wherein the formula IIa and IIb are the equilibratetautomers as a common phenomenon of diketone. In some embodiments thecompound is selected from the group consisting of II-1, II-2, II-3, II-4and II-5. The formulas provided as:

In another aspect of the present invention, a compound is providedaccording to formula IIc:

wherein 1) R₃, R₄, R₃′, and R₄′ are independently selected from thegroup consisting of —H, —OH, and —OCH₃; and 2) R₁, and R₂ areindependently selected from the group consisting of —H, —CH₃, —C₂H₅, asubstituted aryl and a substituted benzyl group.

In another aspect of the present invention, a compound is providedaccording to formula III:

wherein R₃, R₄, R₃′, R₄′, R₃″, and R₄″ are each independently selectedfrom the group consisting of alkoxy, hydroxy, and hydrogen. Nonlimitingexamples include those with the formula III-1 or III-2:

In another aspect of the present invention, a compound is providedaccording to the formula IV:

wherein R₃, R₄, R_(3′), R_(4′) R_(3″), R_(4″), R_(3′″), and R_(4′″) areeach independently selected from the group consisting of alkoxy,hydroxy, and hydrogen. In one embodiment the compound has the formulaIV-1:

In another aspect of the present invention a compound is providedaccording to formula V:

wherein 1) each “n” is independently 1, 2, or 3; 2) R₃, R₄, R₃′, and R₄′are independently selected from the group consisting of —H, —OH, and—OCH₃; 3) L-Z side chain can be no-exist, bur if L-Z side chain exists,L is a C0-C8 alkylene, or an unsaturated alkenylene or alkynl when Z isnothing; 4) Z is selected from the group consisting of —H, —OH, anaromatic ring, a cycloalkyl, —COR₁, —CO₂R₁, —CONR₁R₂, —NR₁R₂, —CX₃; 5)R₁ and R₂ are independently selected from the group consisting of —H,—CH₃, and —C₂H₅; and 6) X is a halogen atom selected from the groupconsisting of —F, —Cl, and —Br. In some embodiments the compounds havethe formula according to V-1 or V-2. The following are representativesof the compounds with formula V-1 and V-2:

Synthesis of the disclosed compounds may be performed using standardpractices known in the organic synthesis arts using known solvents.Synthesized compounds may be tested for desired activity such asdegradation of a steroid receptor, such as the androgen receptor, theability to prevent or inhibit proliferation of cancer cell lines, thereduction of tumor size in grafted animal studies and the like.Compounds identified as hits or leads may be further adapted using thesynthesis methods and techniques disclosed herein. Thus, variations onthe provided synthetic methods will be readily apparent to those skilledin the art and are deemed to be within the scope of the presentinvention.

Example 1 demonstrates a variety of synthesis schemes for the providedmonomers as well as derivatives thereof, which are also encompassedherein. In some embodiments derivatives are provided as a combination ofmonomers or portions thereof to form a biphenyl, triphenyl, orquadrophenyl ring system or more.

In many embodiments, a biphenyl ring system was utilized for testing andcomparison to other proposed treatments; however compounds having asingle (substituted phenyl)-propenal moiety, were also found to haveactivity such as the ability to prevent proliferation of cancer celllines stimulated with DHT and the ability to degrade the androgenreceptor. Some of the compounds of the present invention were preparedthrough a condensation of substituted benzaldehydes and 2,4-pentanedioneor 3-substituted 2,4-pentanedions by the method known in the literature.Pedersen et al., Liebigs Ann. Chem., 1557-1569 (1985). The desiredsubstituents on the biphenyl ring and on the C4 of the conjugationbridge were synthesized either before or after the condensation. Thelength of conjugating bridge between the two phenyl moieties could bevaried from 5 carbons to 11 carbons through synthetic strategies.Properly adding and removing protecting groups allow ultimate synthesisof disclosed compounds.

Several analogues and derivatives of compounds having a (substitutedphenyl)-propenal moiety have been newly synthesized and evaluated forthe anti-androgenic activity. The structure information of some but notall of the disclosed compounds is summarized in FIG. 2.

After extensive study of the structure and biological activity of4-monosubstituted-1,7-bis-(3,4-dimethoxyphenyl)-5-hydroxy-hepta-1,4,6-trien-3-one,it was surprising to find that the 4-substitution(s) at1,7-bis-(substituted-phenyl)-5-hydroxy-hepta-1,4,6-trien-3-onestructures are the more important moiety that are related to the potentanti-androgen and anti-AR activity of these compounds. Another importantstructural feature of this type of compounds is the enol-ketone bridgebetween the two phenyl groups, existing in equilibrium with its diketoneform, which results in the unique molecular intrinsic fluorescence,i.e., the high density of the compound's color. This molecular propertyaffects, in certain degree, pharmaceutical formulation, such assolubility and stability in solvents. In order to reduce the intrinsicfluorescent density, and to improve solubility and stability but not tosacrifice the biological activity, medicinal chemistry and organicsynthesis strategies were used by introducing a second function group,such as a fluoro or methyl group, at C4 position, in addition to theprior mono substitution, to break the extensive molecular conjugationand stabilize the molecule to a distinct diketon form. By using suchstrategy, a series of 4,4-disubstituted1,7-bis-(3,4-dimethoxyphenyl)-hepta-1,6-diene-3,5-dione compounds weresynthesized and biological activity evaluated (FIG. 10). Unexpectedly,these newly synthesized diketone compounds not only have distinguishablyreduced in fluorescent density, but also, more importantly, retainpotent biological activity of anti-androgen and anti-AR activitycomparable to or in some compounds are more potent than their4-mono-substituted counterparts. Another advancement of such structuremodification is an improvement of metabolic stability. For example,structural modification of ASC-Q49 by introducing a methyl group at C4position (see, Compound 6 in FIG. 10) improved its metabolic stabilityand reduced fluorescent density while retained the biological activity.

The innovations presented in this invention provide a more user friendly(i.e., less coloring) topical therapeutics for skin disorders such asacne, alopecia, wound healing and other diseases, disorders andconditions discussed herein and as applicable to the present invention.

In order to improve the physicochemical properties and to manipulate theintrinsic color of compounds, we used medicinal chemistry and organicsynthesis strategies to introduce a second function group, such as afluoro or methyl group, to the C4 position in addition to the prior monosubstitution, thus to break the extensive molecular conjugation andstabilize the molecule to an exclusive diketone form, i.e., no longerco-exist with its enol-ketone tautomer.

By using such strategy, a series of 4,4-disubstituted1,7-bis(3,4-dimethoxyphenyl)-hepta-1,6-diene-3,5-dione compounds aresynthesized and created a further series of compounds of the presentinvention. The biological activity as well as physical and chemicalproperties of these further series of compounds were measured andevaluated. Interestingly and unexpectedly, these newly synthesizeddiketone, i.e., the further series of compounds, their intrinsic deepyellow or dark orange color (under visual light) had dramaticallydiminished or reduced to a light/pale yellow or a whitish color. Thisobservation is evident by the HPLC profile and UV spectrum of compoundASC-Q49 which has a deep orange color and possess two separated tautomerpeaks on HPLC, i.e., one diketone peak with UV maximum at 344 nm (FIG.11A) and the one enol peak with UV maximum at 429 nm (FIG. 11B); whereas“compound 6” (a derivative of ASC-Q49), shows a light yellow color andonly has one diketone peak exhibited UV maximum at 346 nm. (FIG. 11C).This single peak property of these compounds has significantlysimplified the compound analysis and quantification, i.e., byeliminating or reducing the complexity of polymorphism and will benefitthe process of pharmaceutical active ingredient (API) development, andchemical analysis of the API.

Interestingly and unexpectedly, was the finding that most of the furtherseries of compounds have retained their biological activity, i.e.,possess potent anti-androgen and anti-AR activity, comparable to or insome case more potent than their 4-mono-substituted counterparts (Table2). In addition, some compounds were also found to have their metabolicstability significantly improved in acidic condition as wells inbiological fluids (such as human and rats plasmas) (Table 3 throughTable 5). For example, ASC-Q49, an4-monosubstituted-1,7-bis-(3,4-dimethoxyphenyl)-5-hydroxy-hepta-1,4,6-trien-3-oneanalog, was shown as a potent anti-androgen and anti-AR agent (e.g.,FIG. 5). However, its metabolic instability had made it a less idealdrug candidate. However, with the structural modification by introducinga methyl group to the C4 position according to, for example, Formula VIand Formula VII, results in the compound 6 (in FIG. 10) and hadsignificantly improved metabolic stability (Table 4 through Table 5).

The innovative findings presented in this invention can greatly increasethe usefulness of the compounds as drugs (i.e. increase the drugability)and thus benefit the therapeutic drug development. The reduction inintrinsic color of the compounds also increased the potential ofdevelopment of these further series of compounds into topical drugs thatcould avoid the potential skin discoloration and make them more userfriendly.

C. Pharmaceuticals and Cosmetics Including Compounds Having at Least One(Substituted Phenyl)-Propenal Moiety

The present invention includes the disclosed compounds themselves, aswell as their salts and their prodrugs, if applicable. The salts orprodrugs should retain a portion of the desired biological activity ofthe parent compound or be provided in a form that the body or subjectcan convert to a biologically active form. The salts, for example, canbe formed between a positively charged substituent (e.g., amino) on acompound and an anion. Suitable anions include, but are not limited to,chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate,methanesulfonate, tartrate, trifluoroacetate, and acetate. Likewise, anegatively charged substituent (e.g., carboxylate) on a compound canform a salt with a cation. Suitable cations include, but are not limitedto, sodium ion, potassium ion, magnesium ion, calcium ion, and anammonium cation such as teteramethylammonium ion. Nonlimiting examplesof prodrugs include esters and other pharmaceutically acceptablederivatives, which, upon administration to a subject, are capable ofproviding the compounds derivatives described above.

The compounds of the present invention may be formulated foradministration for the prevention or treatment of a variety of medicalconditions. Pharmaceutical formulations may include at least one of thedisclosed compounds or pharmaceutically acceptable salt thereof incombination with a pharmaceutically acceptable carrier. Techniques ofpharmaceutical production are well known in the art of the presentinvention and typically include mixing a compound or salt in thepresence of a suitable carrier. Suitable carriers for use with thecompounds of the present invention include diluents, excipients, orcarrier materials, selected according to the intended form ofadministration and consistent with conventional pharmaceutical orcosmetic practice. Examples of suitable carriers include, but are notlimited to, wate, physiological saline, phosphate-buffered saline, aphysiologically compatible buffe, saline buffered with a physiologicallycompatible salt, a water-in-oil emulsion, and an oil-in-water emulsion,an alcohol, dimethylsulfoxide, dextrose, mannitol, lactose, glycerin,propylene glycol, polyethylene glycol, polyvinylpyrrolidone, lecithin,albumin, sodium glutamate, cysteine hydrochloride, and the like, andmixtures thereof. Suitable carriers can also include appropriatepharmaceutically acceptable antioxidants or reducing agents,preservatives, suspending agents, solubilizers, stabilizers, chelatingagents, complexing agents, viscomodulators, disintegrating agents,binders, flavoring agents, coloring agents, odorants, opacifiers,wetting agents, pH buffering agents, and mixtures thereof, as isconsistent with conventional pharmaceutical practice (“Remington: TheScience and Practice of Pharmacy”, 20th edition, Gennaro (ed.) andGennaro, Lippincott, Williams & Wilkins, 2000).

The pharmaceutical and cosmetic formulations may be provided dependingon the desired route of administration using methods known in thepharmaceutical and cosmetic arts. Suitable routes of administration mayinclude oral, intestinal, parenteral, transmucosal, transdermal,intramuscular, subcutaneous, rectal, intramedullary, intrathecal,intravenous, intraventricular, intraatrial, intraaortal, intraarterial,or intraperitoneal administration.

The pharmaceutical compositions of the present invention can beadministered to the subject by a medical device, such as, but notlimited to, implantable devices, biodegradable implants, patches, andpumps. Where such a device is used, the compositions may be formulatedto include a dissolvable or nondissolvable matrix or medium (forexample, a coating, membrane, film, impregnated matrix, polymer, sponge,gel, or porous layer on or within the medical device) to permit therelease of the active compound or compounds over a specified period oftime.

For use in a living, whole organism, such as in a human subject,compositions of the present invention can be formulated and provided inany formulation suitable to the intended form of administration andconsistent with conventional pharmaceutical practice (“Remington: TheScience and Practice of Pharmacy”, 20^(th) edition, Gennaro (ed.) andGelman), Lippincott, Williams & Wilkins, 2000). Examples of suitableformulations include tablets, capsules, syrups, elixirs, ointments,creams, lotions, sprays, aerosols, inhalants, solids, powders,particulates, gels, suppositories, concentrates, emulsions, liposomes,microspheres, dissolvable matrices, sterile solutions, suspensions, orinjectables, and the like. Injectables can be prepared in conventionalforms either as liquid solutions or suspensions, as concentrates orsolid forms suitable for solution or suspension in liquid prior toinjection, or as emulsions.

D. Medical Treatments Incorporating Compounds Having at Least One(Substituted Phenyl)-Propenal Moieties

Compounds of the present invention were tested for their effect onsteroid receptors and their effect on cancer cell populations. It wasfound that compounds of the present invention were able to reduceandrogen receptor expression (see, FIG. 3 and FIG. 4). Furtherinvestigation demonstrated that compounds of the present invention wereable to inhibit cancer cell growth (see, FIG. 5) and reduce expressionof the androgen receptor within cancer cells (see, FIG. 6 and FIG. 8).The inventors also considered potential mechanisms of action orpotential pathways. FIG. 7 supports the inventors' beliefs that thecompounds of the present invention induce degradation of the androgenreceptor. Thus the activities demonstrated herein support therapeutic orprophylactic treatment against medical conditions such as a variety ofcancers and androgen associated disorders.

The present invention includes methods of treating, amelioratingsymptoms from or preventing the progression of a variety of medicalconditions using the disclosed compounds and compositions, includingpharmaceutical and cosmetic formulations. The medical conditions may, atleast in part, be modulated by a steroid receptor. Steroid receptors ofparticular interest may include but are not limited to androgen receptor(AR), progesterone receptor (PR), estrogen receptor (ER), glucocorticoidreceptor (GR), peroxisome proliferator-activated receptor (PPAR),retinoic acid receptors (RARs and RXRs), and orphan steroid hormonereceptors. Compositions or compounds of the present invention may targeta specific receptor, such as the androgen receptor or may targetparticular receptors within the steroid receptor superfamily.

The methods of the present invention may prevent, treat or amelioratesymptoms from cancers such as but not limited to prostate cancer, livercancer, bladder cancer, cervical cancer, lung cancer and breast cancer,skin cancer, small cell lung cancer, testicular cancer, lymphoma,leukemia, esophageal cancer, stomach cancer, colon cancer, endometrialcancer, ovarian cancer, central nervous system cancer, and the like. Themethods of the present invention may induce cytotoxicity against tumorcells or may inhibit tumor cell growth. Determining whether a compoundor pharmaceutical is beneficial for the treatment or prevention of aparticular disease may include testing the compounds or theirderivatives in vitro, in vivo in an animal model or with a cell-basedassay on a suitable cell line. In the instance of cancer, cell lineshaving a profile of a cancerous cell, such as cell lines prepared fromcancer cells, may be utilized. In some embodiments activities ofcompounds of the present invention are evaluated for the ability toinhibit cancer cell growth or proliferation, optionally stimulated witha stimulator, such as DHT. Compounds disclosed herein were specificallyshown to reduce growth or proliferation of prostate cancer cells.

In other embodiments, the compounds their derivatives, pharmaceuticalcompositions and the like are used to prevent, treat or amelioratesymptoms from neurological and neuromuscular disorders such as KennedyDisease. Spinal and bulbar muscular atrophy (SBMA), or Kennedy'sdisease, is a gender-specific motor neuron disease that affects 1 inevery 40,000 males (reviewed by Katsuno et al., 2004). SBMA patientshave a mutated androgen receptor containing an expanded polyglutaminetract. The expanded polyglutamine androgen receptor forms aggregatesthat interfere with cell functioning and is the factor that causes theproximal muscle atrophy associated with SBMA. The methods of the presentinvention may include relieving the stress caused by aggregate formationby reducing the amount of the mutant AR to a level that could be moreeasily policed by the cells' native housekeeping machinery. The methodsof the present invention may including selectively degrading theandrogen receptor and thus may be used as a therapy for SBMA. Thedisclosed compounds that can enhance androgen receptor degradation maysuppress the steady-state level of the receptor thus, attenuating theseverity of aggregate formation in patients.

Compounds and compositions of present invention may prevent, treat orameliorate symptoms from androgen related hair disorders. For example,androgenetic alopecia or “male pattern baldness” is hair loss caused byandrogen activity on the androgen receptors in follicles and adjacentcells. As another example, hirsutism is excessive growth of thick darkhair in locations where hair growth in women usually is minimal orabsent. Such male-pattern growth of terminal body hair usually occurs inandrogen-stimulated locations, such as the face, chest, and areolae.Methods of the present invention may include administering a compound,pharmaceutical or cosmetic formulation to an individual in need of suchtreatment or prevention.

Compounds and compositions of the present invention may treatinflammation (e.g., rheumatoid arthritis), acne, alopecia, and mayaccelerate wound healing. Acne is caused by androgen-induced ARactivation of sebaceous glands and may therefore be treated byadministering a compound capable of preventing or decreasing ARactivation. Compounds of the present invention are believed to inducedegradation of the androgen receptor and thus would provide an effectivetreatment against such medical conditions. Androgenetic alopecia andother hair growth disorders are known to cause by the activation ofandrogen receptors (AR) in hair follicles by endogenous androgen.Certain inflammation conditions and wound healing are also believed tobe associated with the androgen receptor in response to androgen.Methods of the present invention may include administering a compound,pharmaceutical or cosmetic formulation to an individual in need of suchtreatment or prevention. Topical application of such formulations may beof particular interest.

Compounds and compositions of the present invention may be used in thetreatment of endocrine disorders. Androgen excess is one of the mostcommon endocrine disorders in women (reviewed by Bulun and Adashi,2003). This pathophysiological status can be found in women with variousendocrine disorders, including polycystic ovary syndrome (PCOS),pituitary adenoma-induced hyperprolactinemia, Cushing's syndrome,congenital adrenal hyperplasia, non-classical adrenal hyperplasia, ovaryor adrenal tumor, and iatrogenic androgen excess. Among these disorders,PCOS, occurring in 5-10% of reproductive-age women, is the mostfrequently identified cause of hyperandrogenism. Recently, a relativeincrease in the ratio of circulating androgens to circulating estrogens(named as androgenicity) has been observed in post-menopausal women (Leeet al., 2004). Androgenicity is the consequence of a greater decrease inestradiol and estrone synthesis than that of androgen synthesis aftermenopause, and its clinical implications are under active study. It hasbeen shown that women exhibiting androgenicity are more frequently seenwith central obesity (Peohlman et al., 1995). Fat deposit in theabdominal wall is metabolically active and is associated with insulinresistance in the peripheral tissues (Evans et al., 1983). Other thanthe above-mentioned endocrine disturbances, hyperandrogenie symptoms canalso be detected in human immunodeficiency virus (HIV)-infected womenshowing lipodystrophy syndrome (Hadigan et al., 2000). It has beensuggested that hyperandrogenism may be involved in lipid aberrationsobserved in the latter group of patients.

The methods of the present invention include the treatment of a varietyof medical conditions as disclosed herein or are believed to beassociated at least in part with a steroid or steroid associateddisorder. The methods of treatment include administering a compound,pharmaceutical formulation or cosmetic formulation of the presentinvention to an individual or subject in need thereof. Subjects may betreated with a therapeutically effective dosage. A therapeuticallyeffective dosage may vary somewhat from compound to compound, patient topatient, and will depend on the condition of the patient and route ofdelivery. As general guidance, a dosage from about 0.1 to about 50 mg/kgmay have therapeutic efficacy, while still higher dosages potentiallybeing employed.

Many of the features of the present invention are explained in greaterdetail in the following non-limiting examples. Thus the followingexamples are provided to further illustrate the various aspects andembodiments of the present invention. It is be understood; however, thatthe invention as fully described herein and as recited in the claims isnot intended to be limited by the details of the following examples.

EXAMPLES Example 1 Preparation of Compounds and Derivatives Having atLeast One (3,4-alkoxy or hydroxy Substituted phenyl)-propenal Moiety

In some embodiments, compounds composed of a single (substituted phenyl)propenal core structural unit (monomers) were prepared through standardand advanced organic syntheses. In some embodiments, compoundsconsisting of two or more (substituted phenyl) propenal core structuralmoieties were prepared by a condensation of substituted benzaldehydesand 2,4-pentanedion or 3-substituted 2,4-pentanedions by the methodknown in the literature. Pedersen et al. (Liebigs Ann. Chem., 1557-1569,1985). The desired substituents on the biphenyl ring and on the C4 ofconjugation bridge were synthesized either before or after thecondensation. The length of conjugation bridge between the two phenylmoieties could be varied from 5 carbons to 11 carbons through syntheticstrategies. Properly adding and removing protecting groups allowultimate synthesis of the disclosed derivatives. In addition, varioussynthetic steps may be performed in an alternate sequence in order togive the desired compounds.

Derivative phosphate prodrugs were further prepared by reactingcompounds having compounds a (substituted phenyl)-propenal moiety withphosphorous oxychloride in an appropriate solvent, e.g.,dichloromethane, in the presence of an organic base, e.g.,triethylamine. Tartrate of disclosed compounds as water-soluble saltswere synthesized by reacting compounds having a (substitutedphenyl)-propenal moiety with tartaric acid in water.

Chemical Synthesis

Melting points were determined on a Fisher-John melting point apparatusand are uncorrected. Proton Nuclear Magnetic Resonance (¹H NMR) and ¹³CNMR spectra were measured on Varian Gemini 300 or Inova 500spectrometers with tetramethylsilane (TMS) as the internal standard. ³¹PNMR was conducted on 500 MHz Varian Inova spectrometer using phosphoricacid as external standard. Chemical shifts are reported in δ (ppm). Massspectra (MS) were obtained on an Agilent 1100 series LC-MSD-Trap orPE-Sciex API-3000 spectrometers. Flash column chromatography wasperformed on silica gel (100-200 mesh) or alumina (aluminum oxide,basic, Brockmann I, standard grade, ˜150 mesh). HPLC was conducted onShimadzu SCL 10A instrument. HPFC was conducted on a Biotage system orISCO Inc. Chemflash chromatographic system. Preparative thin layerchromatography (PTLC) on silica gel plates (Kieselgel 60, F254, 1.00 mm)were also used for separation and purification. Precoated silica gelplates (Kieselgel 60, F254, 0.25 mm) were used for thin layerchromatography (TLC) analysis. ASC-J9 was synthesized as startingmaterial by reaction of 3,4-dimethoxybenzaldehyde with 2,4-pentanedionebased on a published method (Pedersen et al., Liebigs Ann. Chem.,1557-1569, 1985).

Synthesis of Monomers 1, 3, 5-7

The monomers, structurally with a (3,4-dimethoxy or 3-methoxy, 4-hydroxysubstituted phenyl)-propenal moiety, a basic structure of the currentlyprovided compounds, have been synthesized by reaction of3-(3′,4′-Dimethoxy-phenyl)-acrylic acid with corresponding reagents(monomers 1, 3), or reaction of 3,4-dimethoxy-benzaldehyde or3-methoxy-4-hydroxy benzaldehyde with ethyl levulinate (monomers 5 and6). Monomer-7 was synthesized starting from3-(3,4-dimethoxyphenyl)propane through two steps. More specifically, thesynthesis methods for the monomers are described as below andillustrated in Scheme 1.

Monomer 1,3-(3′,4′-Dimethoxy-phenyl)-acrylic acid methyl ester, wassynthesized by reaction of 3-(3′,4′-Dimethoxy-phenyl)-acrylic acid withmethanol in the presence of acetic chloride. After refluxing for 2.5 h,the reaction mixture was concentrated by evaporation to 1/3 and thewhite solid was filtered and dried in vacuo to get the desired productin 76% yield as a white crystalline solid. mp.74-75° C. ESI MS m/z:223.0 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.64 (d, 1H, J=15.9 Hz, H-3),7.11 (dd, 1H, J=6.9, 2.1 Hz, H-6′), 7.05 (d, 1H, J=2.4 Hz, H-2′), 6.85(d, 1H, J=8.4 Hz, H-5′), 6.32 (d, 1H, J=15.9 Hz, H-2), 3.92 (s, 6H,phenyl OCH₃), 3.80 (s, 3H, ester OCH₃).

Monomer 3, a mixed anhydride, was prepared by reaction of3-(3′,4′-Dimethoxy-phenyl)-acrylic acid in toluene/CH₂Cl₂ (1:1) in thepresence of Et₃N. The solution was cooled to 0° C., ethyl chloroformate(1.5 eq.) was added dropwise. After stirring at 0° C. for 2 h, theprecipitate was filtered out. The filtrate was concentrated to get arelatively pure white solid, which was purified by a fast filtrationthrough a thin silica gel pad and eluted with hexanes:ethyl acetate (1:0to 4:1) to afford the desired product as a white solid in quantity. ESIMS m/z: 281.0 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.78 (d, 1H, J=15.9 Hz,H-3), 7.15 (dd, 1H, J=8.4, 1.8 Hz, H-6′), 7.06 (d, 1H, J=1.8 Hz, H-2′),6.89 (d, 1H, J=8.4 Hz, H-5′), 6.29 (d, 1H, J=15.9 Hz, H-2), 4.37 (q, 2H,J=6.9 Hz, OCH ₂CH₃), 3.92 (d, 6H, J=1.2 Hz, phenyl OCH₃), 1.40 (t, 3H,J=7.2, OCH₂CH ₃).

Monomer 5, i.e., 6-(3′,4′-Dimethoxy-phenyl)-4-oxo-hex-5-enoic acid ethylester, was synthesized by reaction of 3,4-dimethoxy-benzaldehyde withethyl levulinate as shown in Scheme 1. Ethyl levulinate (1 eq.) reactedwith boron oxide (0.7 eq) in ethyl acetate at 40° C. for 30 min. To theresulting mixture tributyl borate and 3,4-dimethoxy-benzaldehyde (both 1eq.) were added and the mixture was stirred at 40-42° C. for 30 min. Asolution of butyl amine (0.7 eq) in ethyl acetate was added slowly andthe mixture was further allowed to stir at 40-42° C. overnight. 5%hydrochloride acid (1.3 eq) was added and the reaction mixture wasstirred at 60° C. for 1 h. The reaction mixture was cooled to r.t. andwas partitioned. The aqueous portion was extracted with ethyl acetatetwice. The combined ethyl acetate extract was washed with water to pH 4and dried over MgSO₄. After filtration and concentration, the crude waspurified by PTLC to give monomer 5 as white solid. mp.62-63° C. ESI MSm/z: 293.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.55 (d, 1H, J=16.2 Hz,H-6), 7.14 (dd, 1H, J=9.0, 2.1 Hz, H-6′), 7.08 (d, 1H, J=1.8 Hz, H-2′),6.88 (d, 1H, J=8.4 Hz, H-5′), 6.65 (d, 1H, J=16.2 Hz, H-5), 4.16 (q, 2H,J=6.9 Hz, OCH ₂CH₃), 3.93 (s, 6H, phenyl OCH₃), 3.01 (t, 2H, J=6.6 Hz,H-3), 2.69 (t, 2H, J=6.6 Hz, H-2), 1.27 (t, 3H, J=6.9, OCH₂CH ₃).

Monomer 6,6-(4-Hydroxy-3-methoxy-phenyl)-4-oxo-hex-5-enoic acid ethylester, was synthesized by reaction of vanillin with ethyl levulinatewith a similar method recorded in the synthesis of Monomer 5. Thedesired compound was obtained as a yellow crystalline solid. mp.55-56°C. ESI MS m/z: 279.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.54 (d, 1H,J=15.0 Hz, H-6), 7.12-7.06 (m, 2H, aromatic-H), 6.94 (d, 1H, J=8.1 Hz,aromatic H-5′), 6.63 (d, 1H, J=15.0 Hz, H-5), 4.16 (q, 2H, J=7.2 Hz, OCH₂CH₃), 3.94 (s, 3H, phenyl OCH₃), 3.01 (t, 2H, J=6.9 Hz, H-3), 2.69 (t,2H, J=6.9 Hz, H-2), 1.27 (t, 3H, J=7.2, OCH₂CH ₃).

Monomer 7, i.e., 7-(3,4-Dimethoxy-phenyl)-hept-6-ene-2,5-dione was madeby 3-(3,4-dimethoxyphenyl)propane through 2 steps.3,4-dimethoxycinnamaldehyde was made as described in the synthesis ofQ110 (Scheme 13) in 60% yield. Dissolving the resulting compound (1 eq.)in dry EtOH, 3-butene-2-one (1 eq.) was added. The reaction solution washeated to 80° C. under N₂,3-Benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazoliumchloride (0.1 eq.),TEA (0.4 eq.) in EtOH was added dropwise. The resulting reaction mixturewas stirred at the temperature for 10 h, then evaporated to get a yellowoily residue. The crude was dissolved in CH₂Cl₂ and washed with 0.5%H₂SO₄, 2% NaHCO₃, and brine. After drying over Na₂SO₄, the crude waspurified by chromatography though an Al₂O₃ flash column, followed bycrystallization from ethyl ether and pentane to afford the targetcompound as an off-white solid. mp.71-73° C. ESI MS m/z: 263.0 [M+H]⁺;¹H NMR (300 MHz, CDCl₃) δ: 7.55 (d, 1H, J=16.2 Hz, H-6), 7.14 (dd, 1H,J=9.9, 2.1 Hz, H-6′), 7.08 (d, 1H, J=1.8 Hz, H-2′), 6.88 (d, 1H, J=8.4Hz, H-5′), 6.64 (d, 1H, J=16.2 Hz, H-5), 3.93 (s, 6H, phenyl OCH₃), 2.98(t, 2H, J=6.0 Hz, H-3), 2.83 (t, 2H, J=6.0 Hz, H-3), 2.24 (s, 3H, COCH₃).

Synthesis of Compounds Q9, Q44, Q49, Q50, Q77, and Q98

In order to study the effect of C4-substitution of the compounds on ARactivity, a verity of C4-substituted compounds with different functionalgroups (e.g., hydroxyl, ester and amide, etc) were synthesized. Thesecompounds were prepared by treatment of1,7-Bis-(3,4-dimethoxy-phenyl)-5-hydroxy-hepta-1,4,6-trien-3-one(ASC-J9), synthesized through the method described in Scheme 2 with anappropriate bromide or chloride compound (or with ethylene oxide as analternative for making compound Q9) in basic condition.

Compounds Q9 was synthesized as follows. To a 1N NaOH aqueous solution(0.2 mL, 0.2 mmol) containing 0.1 mmol of tetrabutylammonium bromide(phase transferring catalyst, PTC) was added ASC-J9 (0.1 mmol) in CH₂Cl₂(0.5 mL). The mixture was stirred at room temperature for 10 min and2-bromoethane alcohol (0.2 mmol) or ethylene oxide (25 mmol) was added.The resulting reaction mixture was stirred at 40° C. overnight forcompound Q9. The two layers were separated, and the aqueous wasextracted with CH₂Cl₂ 3 times. The combined organic layer was dried overNa₂SO₄ and concentrated. The crude residue was purified by PTLC andrecrystallized from EtOAc. Analytical data for compound Q9 is shownbellow.

Compound Q9: Yellow crystalline solid (EtOAc), mp. 149-150° C. ESI MSm/z: 441.3 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.63 (d, 1H, J=15.9 Hz,H-1), 7.53 (d, 1H, J=15.9 Hz, H-7), 7.14-7.04 (m, 4H, aromatic ring H),6.88-6.85 (2H, aromatic ring H), 6.65 (d, 1H, J=15.9 Hz, H-2), 6.31 (d,1H, J=15.9 Hz, H-6), 4.29 (t, 2H, J=12, and 6 Hz, CH₂ CH ₂OH), 3.94-3.88(12H, OCH₃), 2.84-2.79 (t, 1H, C4-H), 2.14-2.10 (m, 2H, CH ₂CH₂OH).

Compounds Q44, Q49, Q77 were synthesized by reacting ASC-J9 in CH₂Cl₂ orTHF with an appropriate bromide or chloride compound in the presence ofK₂CO₃ and Cs₂CO₃ (9:1) or NaH as shown scheme 2. For the examples ofmaking compounds Q49 and Q77. To a solution of NaH (4 eq.) in THF wasadded ASC-J9 (1 eq.) at 0° C. The resulting solution was stirred at 0°C. for 0.5 h then room temperature for 1.5 h.2-Chloride-N,N-diethylacetamide (4 eq.) (for Q49) or2-Chloride-N,N-dimethylacetamide (4 eq.) (for Q77) were added. Theresulting mixture was heated to reflux overnight. The reaction mixturewas cooled to r.t. (room temperature), diluted with EtOAc, and washedwith 10% H₂SO₄ aq. The organic layer was further washed with sat.NaHCO₃, H₂O and brine, and dried over Na₂SO₄. The desired product waspurified by flash column chromatography and crystallized from EtOAc.

Compound Q49: Yellow crystalline solid, mp. 166-167° C. ESI MS m/z:510.7 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.68 (d, 2H, J=15.9 Hz, H-1,7),7.16-7.06 (4H, aromatic ring H), 6.87-6.84 (2H, aromatic ring H), 6.80(d, 2H, J=15.9 Hz, H-2,6), 4.97 (t, 1H, J=12.0 and 6.0 Hz, C4-H),3.92-3.89 (12H, OCH₃), 3.43-3.33 (m, 4H, CH₂CON(CH ₂CH₃)₂), 3.04 (d, 2H,J=6.6 Hz, C4-CH ₂CON(CH₂CH₃)₂), 1.24 (t, 3H, CH₂CON(CH₂CH ₃)₂), 1.09 (t,3H, CH₂CON(CH₂CH ₃)₂).

Compound Q77: Yellow crystalline solid, mp. 155-157° C. ESI MS m/z:482.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.68 (d, 2H, J=15.6 Hz, H-1,7),7.16-7.06 (4H, aromatic ring H), 6.87-6.83 (2H, aromatic ring H), 6.77(d, 2H, J=15.6 Hz, H-2,6), 4.92 (t, 1H, J=13.5 and 6.6 Hz, C4-H),3.92-3.88 (12H, OCH₃), 3.09-3.04 (m, 5H, —CH ₂CO and N(CH ₃)), 2.94 (s,3H, N(CH₃)).

Compounds Q50 and Q98 were synthesized to compare their activity withQ44 and Q49 (Scheme 3). To a solution of5-Hydroxy-1,7-bis-(4-hydroxy-3-methoxy-phenyl)-hepta-1,4,6-trien-3-oneand 3,4-dihydro-2H-pyran (20 eq.) in dry dichloromethane was addedpyridinium chlorochromate (PPTS) (0.1 eq.). The resulting solution wasstirred at r.t. for 48 h. The solution was then washed with water. Thesolvent was removed and the resulting compound was purified on Biotagecolumn chromatography. Reaction of the obtained product (Q1) with ethylbromoacetae (Q50) or 2-Chloride-N,N-diethylacetamide (4 eq.) (Q98) inthe presence of K₂CO₃ and Cs₂CO₃ (9:1) then removal of THP protectinggroup by PPTS/EtOH gave the desired products Q50 and Q98 respectively.

Compound Q50: Amorphous. mp.63-65° C. ESI MS m/z: 455.2 [M+H]⁺; ¹H NMR(300 MHz, CDCl3) δ: 7.65 (d, 2H, J=15.9 Hz, H-1,7), 7.19-7.04 (6H,aromatic ring H), 6.72 (d, 2H, J=15.9 Hz, H-2,6), 4.16 (2H, COOCH ₂CH₃),3.96-3.92 (6H, OCH₃), 3.04 (d, 2H, J=7.2 Hz, C4-CH ₂COOCH₂CH₃),1.27-1.23 (3H, COOCH₂CH ₃).

Compound Q98: Amorphous. mp.68-71° C. ESI MS m/z: 482.10 [M+H]⁺; ¹H NMR(300 MHz, CDCl3) δ: 7.65 (d, 2H, J=15.9 Hz, H-1,7), 7.12-7.03 (4H,aromatic ring H), 6.94-6.89 (2H, aromatic ring H), 6.76 (d, 2H, J=15.9Hz, H-2,6), 4.96 (t, 1H, J=13.2 and 6.9 Hz, C4-H), 3.92-3.89 (6H, OCH₃),3.44-3.33 (m, 4H, CH₂CON(CH ₂CH₃)₂), 3.04 (d, 2H, J=6.6 Hz, C4-CH₂CON(CH₂CH₃)₂), 1.25 (t, 3H, CH₂CON(CH₂CH ₃)₂), 1.10 (t, 3H,CH₂CON(CH₂CH ₃)₂).

Synthesis of Compound: Q12

This compound was synthesized starting from a commercially availablesubstituted benzaldehyde with 4-acetyl-5-oxohexanoate as shown in Scheme4.

More specifically, 4-acetyl-5-oxohexanoate was reacted with boron oxide(0.7 eq) in ethyl acetate at 40° C. for 30 min. To the resulting mixturetributyl borate and 3-methyl-4-hydroxy benzaldehyde (both 1.6-1.8 eq)were added and the mixture was stirred at 40-42° C. for 30 min. Asolution of butyl amine (1.5 eq) in ethyl acetate was added slowly andthe mixture was further allowed to stir at 40-42° C. overnight. 10%hydrochloride acid (2.5 eq) was added and the reaction mixture wasstirred at 60° C. for 1 h. The reaction mixture was cooled to r.t. andpartitioned. The aqueous portion was extracted with ethyl acetate twice.The combined ethyl acetate extract was washed with water to pH˜4 anddried over MgSO₄. After filtration and concentration, the crude waspurified by silica gel column chromatography (HPFC) with hexanes:ethylacetate as eluent and crystallized from ethyl acetate.

Synthesis of Compounds: Q30, Q35, and Q70

To study the function of di-ketone group in AR activity, a series ofcompounds with an imine group replacing one of ketones were synthesized.

Compounds Q30, Q35 were synthesized by reaction of ASC-J9 withappropriate amines in the presence of BF₃.OEt₂ (Scheme 5). For example,to a solution of ASC-J9 in 1,2-dichloroethane, N,N-diethylamine(compound Q30) (1.2 eq.) was added. The resulting solution was cooled to−30° C. and fresh BF₃.OEt₂ (2 eq.) was added dropwise. The mixture wasstirred under nitrogen at −30° C. to room temperature with TLCmonitoring. After quenching with the addition of pyridine (approximately3 eq.) the mixture was washed with brine and dried over MgSO₄.Evaporation of the solvent and purification with flash columnchromatography yielded the desired product Q30. ESI MS m/z: 452.4[M+H]⁺.

Compounds Q70 was synthesized by reaction of ASC-J9 (0.75 mmol) with(R)-(−)-2-phenylglycinol (1.16 mmol) in anhydrous toluene as shown inthe scheme 5. The reaction mixture was heated to reflux with aDean-Stark trap overnight. The solvent was evaporated, and ethyl acetatewas added and re-evaporated. The obtained crude was purified by columnchromatography on Biotage system to afford the desired product Q70 as alight yellow solid. ESI MS m/z: 516.4 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ:7.54 (d, 1H, J=15.6 Hz, H-1), 7.40-7.28 (5H, aromatic ring H), 7.13 (d,1H, J=15.9 Hz, H-6), 7.16-7.09 (2H, aromatic ring H), 6.95-6.80 (4H,aromatic ring H), 6.68 (d, 1H, J=15.6 Hz, H-2), 6.63 (d, 1H, J=15.9 Hz,H-7), 5.63 (s, 1H, C4-H), 3.94-3.83 (m, 15H).

Synthesis of Compounds: Q99, Q106, Q113, JM2, and JM20

In the continually exploring the effects of C4 side chain on ARactivity, a series of compounds with a carbonyl group containingC4-substitutions were synthesized. Compound Q99 was synthesized byreaction of ASCJ-9 with 3-Chloro-2-methoxymethoxy-propene, followed byremoval of methoxymethyl group as showed in Scheme 6. More specifically,an aqueous solution of NaOH (2 eq.) and tetrabutylammonium bisulfate(TBABS) was stirred for 5 min. To the reaction solution was added asolution of ASCJ-9 (1 eq.) in 1,4-dioxane dropwise at rt and theresulting red two phased-mixture was stirred at rt. for 10 min. To thismixture was added 3-Chloro-2-methoxymethoxy-propene (1.5 eq) in1,4-dioxane and the resulting solution was stirred at rt. for 5 min thenat 70° C. overnight. The solid was removed by filtration and thefiltrate was concentrated to dryness. The resulting residue wassuspended in 1% H₂SO₄/dioxane (2:1, volume) and the suspension wasstirred at rt. for 4 h with TLC monitoring. The reaction mixture wasextracted with CH₂Cl₂, dried over Na₂SO₄, filtered and concentrated. Thecrude was purified by flash column chromatography and eluted withhexanes/EtOAc mixture to give the desired product as a yellowcrystalline solid. M.p. 163-166° C. ESI MS m/z: 453.1 [M+H]⁺.

Compounds Q106 and Q113 was synthesized with the method described formaking the compound Q44 in Scheme 2. An example to make Q106 wasdescribed as below. To a solution of ASC-J9 (0.25 mmol) in dry CH₂Cl₂ (5mL) was added 2-bromo-1-phenyl-ethanone (1.2 eq.), K₂CO₃/Cs₂CO₃ (10:1)(˜2 eq.). The reaction mixture was stirred at 11 overnight with TLCmonitoring. The reaction mixture was diluted with EtOAc and washed withH₂O, then dried over Na₂SO₄. The obtained crude was purified by silicagel flash column chromatography eluted by hexanes and EtOAc mixture toget the desired product.

Compounds Q106, yellow crystal, mp.160-2° C. ESI MS m/z: 515.2 [M+H]⁺.¹H NMR (300 MHz, CDCl₃) δ: 8.14-8.01 (2H, aromatic ring H), 7.74-7.68(2H, H-1,7), 7.65-7.46, (m, 4H, aromatic ring H), 7.18-7.15 (1H,aromatic ring H), 7.09-7.06 (2H, aromatic ring H), 6.91-6.80 (m, 4H,aromatic ring H), 6.69 (d, 2H, J=15.3 Hz, H-2,6), 3.92-3.90 (12H, OCH₃),3.78 (2H, —CH ₂CO).

Compounds Q113, yellow fluffy solid, mp.145-7° C. ESI MS m/z: 479.1[M+H]⁺. ¹H NMR (300 MHz, CDCl₃) 43: 7.75 (d, 1H, J=15.3 Hz, H-1,7),7.20-7.17 (2H, aromatic ring II), 7.07-7.06 (2H, aromatic ring H), 6.90,6.88 (2H, aromatic ring H), 6.86 (1H, J=15.3 Hz, H-2,6), 3.95-3.93 (12H,OCH₃), 3.76 (2H, —CH ₂CO), 2.14-2.05 (m, 1H, cyclopropyl-H), 1.10-1.04(m, 2H, cyclopropyl-H), 0.93-0.86 (m, 2H, cyclopropyl-H).

Compound JM2 was synthesized by reaction of ASC-J9 (40 mg) withiodoacetamide (80 mg) and anhydrous sodium carbonate (40 mg) in dryacetone as showed in Scheme 7. The reaction mixture was heated to refluxfor 24 hours. After cooling, the mixture was filtered to removeinorganic solid and filtrate was evaporated. The obtained crude residuewas purified by preparative silica gel chromatography plate (Ethylacetate only) to afford the desired product as a light yellow solid.

Compound JM2, amorphous; ESI MS m/z: 452.2 [M+H]⁺; ¹H NMR (300 MHz,CDCl3) δ: 7.79 (d, 2H, J=15.3 Hz, H-1, 7), 7.4-6.4 (6H, aromatic ringH), 6.33 (d, 2H, J=15.3 Hz, H-2, 6), 3.93, 3.92 (all s, both 6H, OCH ₃),2.06 (d, J=6.3 Hz, 2H, CH ₂CONH₂).

Synthesis of JM-10

A mixture of 1.0 gram of ASC-J9, 5 ml of acetic anhydride, and 1 ml oftrimethyl orthoformate was stirred at 70° C. for 22 hours (Scheme 7).The solution was then vacuum evaporated to dryness. The residue wasre-dissolved in CH₂Cl₂-ethanol to re-crystallize. Compound JM10 wasafforded as orange-reddish crystals (270 mg); mp. 137-138° C.; ESI MSm/z: 425.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 10.37 (s, 1H, C4-COH),7.94, 7.71 (both d, 2H each, J=15.6 Hz, H-1, 2, 6, 7), 7.26 (dd, 2H,J=1.8, 8.7 Hz, aromatic 5′-H), 7.17 (d, 2H, J=1.8 Hz, aromatic 2′-H),6.91 (d, 2H, J=8.7 Hz, aromatic 6′-H), 3.97, 3.95 (both s, 6H each,OCH₃).

Synthesis of Compound Q100, Q101, JM1, JM6, and JM7

Compounds Q100, Q101, JM1, JM6, and JM7 were made with an unsaturatedside chain at C4 position of ASC-J9 intending to enhance anti-prostatecancer activity. Compound Q100 was synthesized by reaction of ASC-J9with 3-bromo-propyne in CH₂Cl₂ at 60° C. over night in the presence ofK₂CO₃. Compound Q101 was made by reaction of ASC-J9 with bromopropene inDMF at 100° C. for 2 h in the presence of K₂CO₃ and KI (Scheme 8). Thecrude compounds were purified by silica gel flash column chromatographyeluted by hexanes and EtOAc mixture to get the desired products.

Compound Q100, yellow solid amorphous, mp.75-78° C. ESI MS m/z: 453.1[M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ: 7.75 (d, 1H, J=15.3 Hz, H-1), 7.69(d, 1H, J=15.6 Hz, H-7), 7.23-7.05, and 6.91-6.85 (m, 7H, aromatic ringH and H-2), 6.73 (1H, J=15.6 Hz, H-6), 3.96-3.91 (12H, OCH₃), 3.46 (1H,C4-H), 2.96 (s, 1H, acetylene), 2.94-2.90 (dd, 2H, —CH ₂CCH).

Compound Q101, amorphous, mp. 69-72° C. ESI MS m/z: 437.1 [M+H]⁺. ¹H NMR(300 MHz, CDCl₃) δ: 7.71 (d, 1H, J=15.6 Hz, H-1), 7.70 (d, 1H, J=15.6Hz, H-7), 7.18-7.12 (m, 2H, aromatic ring H), 7.06-7-7.00 (m, 2H,aromatic ring H), 6.90-6.85 (2H, aromatic ring H), 6.85 (1H, J=15.6 Hz,H-2), 6.67 (1H, J=15.6 Hz, H-6), 5.64-5.49 (m, 1H, ethylene H),5.19-5.07 (m, 2H, ethylene H), 3.94-3.91 (m, 12H, OCH₃), 296 (d, 2H, —CH₂—).

Compound JM1 was synthesized by reaction of ASC-J9 (40 mg) with cinnamylbromide and anhydrous sodium carbonate in dry acetone (Scheme 9). Thereaction mixture was heated to reflux for 24 hours. After cooling, themixture was filtered to remove inorganic solid and filtrate wasevaporated. The obtained crude was purified by preparative silica gelchromatography plate (n-Hexane-Ethyl acetate=1:1) to afford the desiredproduct JM1 as a light yellow solid. Amorphous; ESI MS m/z: 513.4[M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.74 (d, 2H, J=15.3 Hz, H-1,7), 7.32(d, 1H, J=18.6 Hz, —CH2CH═CH—), 7.4-6.4 (11H, aromatic ring H), 6.93 (d,2H, J=15.3 Hz, H-2, 6), 6.46 (d, 1H, J=18.6 Hz, —CH2CH═CH—), 3.91, 3.88(all s, both 6H, OCH ₃), 3.50 (br d, 2H, —CH2CH═CH—).

Compound JM6 was synthesized by reaction of ASC-J9 (60 mg) withbromomethyl acetate (50 mg) and sodium hydroxide (20 mg) in dry acetone(Scheme 9). The reaction mixture was heated to reflux for 24 hours.After cooling, the mixture was filtered to remove inorganic solid andfiltrate was evaporated. The obtained crude was purified by preparativesilica gel chromatography plate (n-Hexane-Ethyl acetate=1:2) to affordthe desired product JM6 as a light yellow solid (ESI MS m/z: 467.3[M+H]⁺).

Compound JM7, obtained as a by-product of JM4 aforementioned, yellowfine crystals from EtOAc/hexanes; mp. 109-110° C.; ESI MS m/z: 545.2[M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.83 (s, 1H, CH═C— at C4), 7.79,7.51, 6.98, 6.83 (all d, 1H each, J=15.5 Hz, H-1, 2, 6, 7), 7.20, 7.15,7.08 (all dd, 1H each, J=1.8, 8.4 Hz, aromatic 5′-H), 6.87 (d, 1H, J=8.4Hz, aromatic 6′-H), 6.83 (d, 2H, J=8.4 Hz, aromatic 6′-H), 7.07, 7.06,6.99 (all d, 1H each, J=1.8 Hz, aromatic 2′-H), 3.92, 3.88 (all s, 6Heach, OCH₃), 3.90, 3.83 (all s, 3H each, OCH₃).

Synthesis of Compounds: Q102-Q104, Q108, Q114-Q115, JM12-JM14, andJM16-JM19

Compounds Q102-Q104, Q108, JM12-JM14, JM17 were synthesized to evaluatethe properties of the C4-alkyl substitution on ASC-J9 with differencesin chain length, in ring size, and in functional groups at chain-end(e.g., Q108 and JM14). Compounds Q114-Q115, JM16, JM 18-19 weresynthesized to evaluate the functions of not only the C4-side chain butalso the substitutions on the bi-phenyl moiety. All compounds wereprepared by reaction of 2,4-pentadione with appropriate alkyl oralkylene (or substituted alkyl or alkylene) bromide or iodine in benzenewith DBU as a base. The resulting product 3-substituted 2,4-pentadionefurther reacted with 3,4-dimethoxybenzaldehyde or 4-methoxybenzaldehydeor 3-methoxy-4-hydroxybenzaldehyde to afford the desired products(Scheme 10). An example to make Q104 was illustrated as below. Mix2,4-pentadione 0.2 g (2 mmol) and DBU 30 ul (1 eq.) in benzene 3 mL. Tothis solution was added dropwise 0.48 g (1 eq.) of octyl iodine in 1 mLof benzene at r.t. The resulting solution was stirred at r.t. overnight.The reaction mixture was washed with brine and extracted the CH₂Cl₂,dried over Na₂SO₄ and purified by silica gel flash column chromatographyto give a mixture of C3-octanyl substituted 2,4-pentadione and O-octylsubstituted 2,4-pentadione. Reaction of the mixture with3,4-methoxybenzaldehyde through the method mentioned above afforded thecompound Q104.

Compound Q104, yellow solid from EtOAc/hexanes (2:1), mp. 87-90° C. ESIMS m/z: 509.3 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.71 (d, 1H, J=15.6 Hz,H-1), 7.63 (d, 1H, J=15.9 Hz, H-7), 7.21-7.14 (m, 2H, aromatic H),7.08-7.05 (m, 2H, aromatic H), 6.95 (d, 1H, J=15.6 Hz, H-2), 6.91-6.84(m, 2H, aromatic H), 6.73 (d, 1H, J=15.9 Hz, H-6), 3.94-3.91 (m, 12H,—OCH₃), 2.55 (t, 1H, H-4), 1.61-1.22 (m, 12H, butyl group), 0.87 (m, 3H,—CH₃).

Compound Q102, a red needle crystal from EtOAc/hexanes, mp. 162-164° C.ESI MS m/z: 425.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.73 (d, 2H, J=15.3Hz, H-1,7), 7.23-7.19 (dd, 2H, J=8.1, 1.8 Hz, aromatic H), 7.09 (d, 2H,J=1.5 Hz, aromatic H), 6.96 (d, 2H, J=15.3 Hz, H-2, 6), 6.90 (d, 2H,J=8.1 Hz, aromatic ring H), 3.96 (s, 6H, OCH₃), 3.94 (s, 6H, OCH₃),2.66-2.57 (m, 2H, —CH ₂CH₃), 1.24 (t, 2H, J=15.0, 6.0 Hz, —CH₂CH ₂).

Compound Q103, yellow crystal from EtOAc, mp. 125-126° C. ESI MS m/z:453.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.74-7.61 (2H, H-1,7),7.21-7.06 (m, 4H, aromatic H), 6.99-6.71 (4H, H-2,6 and aromatic H),3.94-3.92 (12H, —OCH₃), 2.57 (t, 1H, H-4), 1.51-1.22 (m, 6H,—CH₂CH₂CH₂—), 0.87 (3H, —CH ₃).

Compound Q108, yellow solid from EtOAc, mp, 60-62° C. EST MS m/z: 515.2[M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.72-7.60 (2H, H-1,7), 7.34-7.00 (m,8H, aromatic H), 6.91-6.84 (31-1, aromatic H), 6.82-6.68 (2H, H-2,6),3.95-3.92 (12H, —OCH₃), 3.46 (t, 1H, H-4), 2.80-2.52 (m, 2H, benzyl CH₂), 2.12-1.84 (2H, —CH ₂—), 1.68-1.50 (2H, —CHCH ₂—).

Compound JM12, orange needles from EtOAc/hexanes; mp. 138-139° C.; ESIMS m/z: 451.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.72, 6.99 (both d, 2Heach, J=15.3 Hz, H-1, 2, 6, 7), 7.21 (dd, 2H, J=1.8, 8.4 Hz, aromatic5′-H)), 7.08 (d, 2H, J=1.8 Hz, aromatic 2′-H), 6.90 (d, 2H, J=8.4 Hz,aromatic 6′-H), 5.30 (br. s, 1H, OH), 3.95, 3.93 (both s, 6H each,OCH₃), 2.65 (d, 2H, J=6.0 Hz, C4-CH₂—), 0.95 (m, 1H, CH ofcyclopropane), 0.95 (m, 1H, CH of cyclopropane), 0.51, 0.24 (both m, 2Heach, CH₂ of cyclopropane).

Compound JM13, orange needles from EtOAc/hexanes; mp. 172-174° C.; ESIMS m/z: 493.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.71, 6.97 (both d, 2Heach, J=15.3 Hz, H-1, 2, 6, 7), 7.20 (dd, 2H, J=1.8, 8.4 Hz, aromatic5′-H), 7.08 (d, 2H, J=1.8 Hz, aromatic 2′-H), 6.92 (d, 2H, J=8.4 Hz,aromatic 6′-H), 5.30 (br. s, 1H, OH), 3.95, 3.94 (both s, 6H each,OCH₃), 2.46 (d, 2H, J=6.9 Hz, C4-CH₂—), 1.90-1.00 (m, 1H, 1 CH and 5 CH₂of cyclohexane).

Compound JM14, orange needles from EtOAc/hexanes; mp. 131-132° C.; ESIMS m/z: 493.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 9.87 (br.s, 1H, OH),7.76, 6.90 (both d, 2H each, J=15.3 Hz, H-1, 2, 6, 7), 7.19 (dd, 2H,J=1.8, 8.4 Hz, aromatic 5′-H), 7.10 (d, 2H, J=1.8 Hz, aromatic 2′-H),6.91 (d, 2H, J=8.4 Hz, aromatic 6′-H), 5.30 (br. s, 1H, OH), 3.95, 3.94(both s, 6H each, OCH₃), 2.86, 2.37 (both m, 2H each, C4-CH₂—CH₂—).

Compound JM16, orange amorphous; ESI MS m/z: 437.2 [M+H]⁺; ¹H NMR (300MHz, CDCl₃, 2:1 tautomerism observed, data for major form listed) δ:7.62, 6.71 (both d, 2H each, J=15.9 Hz, H-1, 2, 6, 7), 7.12 (dd, 2H,J=1.8, 8.4 Hz, aromatic 5′-H), 7.05 (d, 2H, J=1.8 Hz, aromatic 2′-H),6.92 (d, 2H, J=8.4 Hz, aromatic 6′-H), 5.96 (br. s, 2H, OH×2), 3.97 (s,3H, OCH₃), 3.94 (s, 9H, OCH₃×3), 2.68 (d, 2H, J=6.9 Hz, C4-CH₂—),2.19-1.59 (m, 7H, 1 CH and 3 CH₂ of cyclobutane).

Compound JM17, orange needle from EtOAc/hexanes mp. 126-127° C.; ESI MS465.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃), δ: 7.72, 7.00 (both d, 2H eachJ=15.3 Hz, H-1, 2, 6, 7), 7.21 (dd, 2H, J=1.8, 8.4 Hz, aromatic 5′-H),7.09 (d, 2H, 1.8 Hz, aromatic 2′-H), 6.92 (d, 2H, J=8.4 Hz, aromatic6′-H), 3.96, 3.95 (both s, 6H each, OCH₃), 2.70 (d, 2H, J=6.9 Hz,C4-CH₂—), 2.08 (m, 2H, 1 CH₂ of cyclobutane), 1.83 (m, 4H, 2 CH₂ ofcyclobutane).

Compound JM18, orange amorphous; ESI MS m/z: 423.2 [M+H]⁺; ¹H NMR (300MHz, CDCl₃, 2:1 tautomerism observed, data for major form listed) δ:7.65, 6.73 (both d, 2H each, J=15.9 Hz, H-1, 2, 6, 7), 7.12 (dd, 2H,J=1.8, 8.4 Hz, aromatic 5′-H), 7.05 (d, 2H, J=1.8 Hz, aromatic 2′-H),6.92 (d, 2H, J=8.4 Hz, aromatic 6′-H), 3.93 (s, 12H, OCH₃×4), 2.71, 2.65(both d, 1H each, J=6.0 Hz, C4-CH₂—), 0.95 (m, 1H, CH of cyclopropane),0.51, 0.24 (both m, 2H each, CH₂ of cyclopropane).

Compound JM19, orange reddish needle from EtOAc/hexanes; mp. 153-154°C.; ESI MS m/z: 465.2 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃), δ: 7.75, 6.88(both d, 2H each, J=15.5 Hz, H-1, 2, 6, 7), 7.17 (dd, 2H, J=1.6, 8.5 Hz,aromatic 5′-H), 7.07 (d, 2H, J=1.6 Hz, aromatic 2′-H), 6.96 (d, 2H,J=8.5 Hz, aromatic 6′-H), 5.90 (s, 2H, OH×2), 3.96 (s, 6H, OCH₃×2),2.86, 2.35 (both in, 2H each, C4-CH₂—CH₂—).

Compound Q114, yellow crystalline solid from EtOAc/hexanes, mp. 166-167°C. ESI MS m/z: 337.0 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.63 (d, 2H,J=16.1 Hz, H-1,7), 7.53-7.50 (m, 4H, aromatic H), 6.94-6.91 (m, 4H,aromatic H), 6.50 (d, 2H, J=16.1 Hz, H-2, 6), 5.79 (s, 1H, H-4), 3.85(s, 6H, OCH₃).

Compound Q115, yellow crystal from EtOAc, mp. 142-143° C. ESI MS m/z:393.1 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.73 (d, 2H, J=15.6 Hz, H-1,7),7.55-7.52 (4H, aromatic H), 6.99-6.92 (6H, H-2,6 and aromatic H), 3.86(6H, —OCH₃), 2.55 (t, 1H, H-4), 1.53-1.40 (m, 6H, —CH₂CH₂CH₂—), 1.01 (t,3H, —CH₃).

Synthesis of Compounds: JM4, JM20, and Q116

Compounds JM4, JM20, Q116 structurally share the property of a(substituted)-triaryl system [three (substituted phenyl) propenalconjugation]. One of the purposes to synthesize these compounds is tostudy the effect of multi-phenyl propenal moiety on anti-AR andanti-prostate cancer activities. Compound JM4 were synthesized from acondensation of 3,4-dimethyoxybenzaldehyde with triacetylmethane asshown in Scheme 11.

Compounds JM20 and Q116 were synthesized with the same method describedas JM4.

Compound JM20, red powder, mp. 165-167° C.; ESI MS m/z: 455.2 [M+H]⁺; ¹HNMR (300 MHz, d₆-DMSO) δ: 7.69 (d, 2H, J=15.6 Hz, H-1,7), 7.03 (d, 1H,J=16.2 Hz, C4 side chain —COCH═CH—), 7.62-7.34 (m, 6H, aromatic ring H),6.67 (d, 1H, J=15.6 Hz, C4 side chain —COCH═CH—), 6.90-6.72 (m, 4H,aromatic H), 6.57 (d, 2H, J=15.9 Hz, H-2,6).

Compound Q116, yellow amorphous solid, mp. 70-72° C. ESI MS m/z: 497.1[M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.78 (d, 2H, J=15.3 Hz, H-1,7), 7.60(d, 1H, J=15.6 Hz, C4 side chain —COCH═CH—), 7.54-7.51 (2H, aromaticring H), 7.47-7.44 (4H, aromatic ring H), 6.97 (d, 1H, J=15.6 Hz, C4side chain —COCH═CH—), 6.92-6.85 (6H, aromatic H), 6.71 (d, 2H, J=15.3Hz, H-2,6), 3.84-3.82 (9H, —OCH₃).

Synthesis of Compound: JM5

Compound JM5 structurally containing four (substituted phenyl) propenalmoieties was synthesized by reaction of ASC-J9 (18.9 g) with bromomethylacetate (10.0 g) in anhydrous acetone (250 mL) in the presence of sodiumcarbonate (5.0 g) (Scheme 12). After heating to reflux for 80 h, thesolid was filtered and the filtrate was concentrated under vacuum. Theresidue was subjected repeated silica gel column chromatography(n-hexanes:ethyl acetate-2:1) to afford the desired product andrecovered starting material ASC-J9 (15 g). The obtained product wasdissolved in 0.5 mL of ethyl acetate and was added dropwise to 5 mL ofhexanes with stirring. After filtration and drying in vacuum to givecompound JM5 (877 mg) as a yellow powder. Compound JM5 was alsosynthesized by reaction of ASC-J9 with bromomethyl methyl ether andsodium carbonate in anhydrous acetone in shorter time and with higheryield.

Analytical data on compound JM5 are shown below.

Yellow amorphous. mp. 111-114° C. ESI MS m/z: 804.87 [M+H]⁺; ¹H and ¹³CNMR data on 500 MHz Varian, (CDCl3) was listed in Table 1.

TABLE 1 ¹H and ¹³C NMR Spectral Data of ASC-JM5.

No. Groups δ ¹H δ ¹³C a1 Ar. ═C 126.83 a2 Ar. ═CH 7.098 (d, J = 1.5)109.62 a3, 4, b3, Ar. ═C(OCH3) *3.812 (s), 3.596, 147.77, 147.93, 4, c3,c4, 3.708, 3.968, 3.950, 148.96, 149.15, d3, 4. 3.946, 3.857, 3.931149.17, 151.25, 151.69, 151.87 a5 Ar. ═CH 6.878 (d, J = 8.0) 110.82 a6Ar. ═CH 7.167 (dd, J = 8.0, 1.5) 123.31 a11 ═CH 7.732 (d, J = 15.5)143.25 a12 ═CH 7.017 (d, J = 15.5) 116.46 a13 C═O 182.21 a14 —CH— 4.317(s)  40.75 b1 Ar. ═C 127.84 b2 Ar. ═CH 6.881 (d, J = 2.0) 109.57 b5 Ar.═CH 6.740 (d, J = 8.0) 110.71 b6 Ar. ═CH 7.081 (dd, J = 8.0, 2.0) 124.09b11 ═CH 7.681 (d, J = 15.5) 145.83 b12 ═CH 6.739 (d, J = 15.5) 118.33b13 C═O 196.29 c1 Ar. ═C 126.80 c2 Ar. ═CH 7.055 (d, J = 1.5) 109.80 c5Ar. ═CH 6.878 (d, J = 8.5) 110.82 c6 Ar. ═CH 7.195 (dd, J = 8.5, 1.5)123.84 c11 ═CH 7.60 (d, J = 15.5) 144.71 c12 ═CH 7.038 (d, J = 15.5)119.03 c13 C═O 194.59 c14 —CH— 4.317 (d, J = 7.5)  40.69 d1 Ar. ═C133.03 d2 Ar. ═CH 6.653 (s) 111.92 d5 Ar. ═CH 6.740 (d, J = 8.5) 110.71d6 Ar. ═CH 6.676 (d, J = 8.0) 120.28 d11 —C—  68.86 d12 —CH₂ 3.268 (d, J= 16.5),  24.13 3.352 (d, J = 16.5) d13 C═O 190.32 d14 —CH₂ 2.734 (d, J= 19.5),  37.74 3.516 (dd, J = 19.5, 7.5) a3, 4, b3, —OCH₃ 3.596 (s), 55.40 4, c3, c4, 3.708 (s), 3.812 (s),  55.59 d3, 4. 3.857 (s), 3.946(s),  55.87 3.931 (s), 3.950 (s),  55.94 3.968 (s)  56.05 *1H data ofthe methoxy protons

Synthesis of Compounds: Q110 and Q111

In order to study the contribution of the length of the conjugationbridge to the AR activity, compound Q110 with a four-conjugated-doublebond linker and compound Q111 with a five-conjugated-double bond linkerwere synthesized and illustrated in Scheme 13. Compound Q110 wassynthesized starting from 1,2-dimethoxy-4-propyl-benzene. To a solutionof 3-(3,4-dimethoxyphenyl) propane in dry dioxane was added with DDQ(3.1 eq.) and catalytic amount of acetic acid. The mixture was sonicatedfor 2 h with TLC monitoring. After completion of the reaction, the solidwas filtered out and the filtration was concentrated. The residue wasdissolved in EtOAc and washed with water, 2% NaHCO₃, and brine. Theorganic extract was dried over Na₂SO₄ and concentrated to afford a crudeas yellow-brownish solid, which was purified with neutral alumina columnchromatography and eluted with hexanes-ethyl acetate mixture to give alight yellow solid, 3,4-dimethoxycinnamaldehyde in 60% yield (B. P.Joshi et al., Tetrahedron, 62, 2590-2593, 2006). A solution of2,4-petanedione (3 eq.) and B₂O₃ (1 eq.) in EtOAc was stirred at 40° C.for 0.5 h, 3,4-dimethoxycinnamaldehyde (1 eq.) and tributyl borane (1eq.) were added. The resulting reaction mixture was stirred at 40° C.for 0.5 h. Butylamine (1.2 eq.) in EtOAc was added dropwise at thetemperature and stirred at 40° C. for 16 h. To the red reaction mixture,1% HCl aq was added and the mixture was stirred to 60° C. for 1 h. Aftercooling to rt, the aqueous was separated and the organic was washed withwater to pH˜7 and dried over Na2SO4. The crude was purified by silicagel flash column chromatography to get the intermediate product8-(3,4-Dimethoxy-phenyl)-4-hydroxy-octa-3,5,7-trien-2-one as anoff-white solid. A solution of the intermediate (1 eq.) and B₂O₃ (0.7eq.) in EtOAc was stirred at 70° C. for 0.5 h. 3,4-dimethoxybenzaldehyde(1 eq.) and trubutyl borane (1 eq.) were added and the reaction mixturewas stirred at 70° C. for 0.5 h. Piperidine (1.2 eq.) in EtOAc was addeddropwise and the reaction mixture was stirred at 88-90° C. for 1 h.After cooling to 60° C., 1% HCl aq was added and the mixture was stirredat 60° C. for 0.5 h. The reaction mixture was worked-up by following theprocedure described above and the crude was purified by silica gelcolumn chromatography to afford the desired product Q110 as a red solid.Amorphous, mp. 65-68° C., ESI MS m/z: 423.1 [M+H]⁺; ¹H NMR (300 MHz,CDCl3) δ: 7.64-7.58 (d, 2H, H-1 and 2), 7.16-7.02 (4H, aromatic ring Hand trans double bond H), 6.90-6.82 (4H, aromatic ring H), 6.53-6.48(1H, trans double bond H), 6.18-6.12 (1H, trans double bond II), 5.75(s, 1H, H-4), 3.94-3.92 (12H, —OCH₃).

Compound Q111 was synthesized by reaction of8-(3,4-Dimethoxy-phenyl)-4-hydroxy-octa-3,5,7-trien-2-one (3) with3,4-dimethoxycinnamaldehyde (2) as described in the synthesis of Q110(Scheme 13). A red amorphous solid was afforded, nap. 187-9° C. ESI MSm/z: 449.1 [M+H]⁺; ¹H NMR (300 MHz, CDCl3) δ: 7.49-7.40 (d, 2H, H-1 and11), 7.06-7.02 (4H, aromatic ring H), 6.87-6.81 (2H, aromatic ring H,and 4H for trans double bond H), 6.17-6.12 (2H, trans double bond H),5.75 (s, 1H, H-4), 3.94-3.92 (12H, —OCH₃).

Example 2 Detecting Biological Effects of Compounds Having at Least One(3,4-Alkoxy or Hydroxy Substituted Phenyl)-Propenal Moiety on HumanAndrogen Receptor (AR) and Androgen/AR-Mediated Activity

Representative ASC compounds and monomers were tested for their activityto block androgen/AR-induced functions. A cell growth assay using humanprostate cancer cells, either LNCaP or CWR22Rv1, was applied in thestudies. Functional AR proteins are expressed in both cancer cell lines;whereas the growth of LNCaP cells is DHT dependant, but the growth ofCWR22Rv1 cells, derived from a relapsed hormone-refractory tumor, wasnot. In addition, Western Blot analysis were performed by testingmonomers, and some representative new compounds in prostate cancer cellsto demonstrate that compounds with at least one(4-hydroxy-3-methoxy-phenyl)-propenal moiety are capable of reducing ARprotein expression levels and inhibiting cancer cell growth in vitro.

In Vitro Cell Growth Assays Using Human Prostate Cancer Cell Lines,LNCaP and CWR22Rv1

The MTT cell proliferation assay was applied in the present invention todetect the capability of compounds to suppress or inhibit prostatecancer cells growth. The MTT assay, which is a method widely used todetect proliferation of culture cells and is relied upon the conversionof a colorless substrate to reduced tetrazolium by a mitochondrialdehydrogenase (possessed by all viable cells), and has been demonstratedpreviously (Su et al., 1999) to assess the growth of varioustissue-cultured cells. Briefly, 1×10³ LNCaP or CWR22Rv1 cells suspendedin complete medium were plated into each well of a 96-well Microtest IIItissue culture plate (Falcon, N.J.). Two days later, the medium wasreplaced with RPMI-1640 medium containing 10% charcoal/dextran-deprivedFBS (hormone-deprived fetal bovine serum). Testing compounds were addedto the medium at indicated concentrations with or without 1 nM DHT andcells were cultured for 5 days in an incubator (at 37° C.). MTTsubstrate solution (5 mg/ml in PBS) in 1/10 of volume was added to thecells in each well at 2 hours before harvesting. After 2 hourincubation, the plates were centrifuged (10 min at 1,000 rpm) and thesupernatant from each well was carefully removed. A 100 μl of lysisbuffer (50% dimethyl formamide, 5% sodium dodecyl sulphate, 0.35 Macetic acid, and 50 in M HCl) was added to each well to lyse the cellsand dissolved tetrazolium in each well. The relative quantity of enzymeactivity from each well was measured based on absorbance read at awavelength of 450 inn using a Bio-RAD BenchMark microplate reader. Dataderived from the MTT assay were also verified by the actual cell countand cell morphology on a separate plate set tip in parallel. Data fromthis parallel plate demonstrated a positive relationship between thequantity of enzyme activity and the number of viable cells in the well.

Western Blot Analysis of AR Protein Expression Levels in Prostate CancerCells

A widely used Western Blotting analysis was employed to measure ARprotein expression level. Human prostate cancer cells, LNCaP andCWR22Rv1, both express high levels of AR proteins and were used in thisstudy. In this invention representative ASC compounds were tested inWestern blot assay to evaluate their activity in reducing AR expression;and the assays were carried out in either the presence or absence ofdihydrotestosterone (DHT, 1 nM). After cells were incubated with testingcompounds for the designated time, they were harvested and lysedaccording to Western Blot techniques known in the biochemical arts.Details of Western Blotting analysis method have been publishedpreviously (Su et al., 1999). Briefly, cells were harvested either in 2×sodium dodecyl sulphate/polyacrylamide gel electrophoresis (SDS/PAGE)loading buffer or in Radio-Immunoprecipitation Assay (RIPA) lysis bufferstrengthened with 10 μg/ml of benzamidine, 10 μg/ml of trypsininhibitor, and 1 in M of phenylmethylsulfonyl fluoride. A sample oftotal protein (approximately 40 μg) from each cell lysate was separatedby electrophoresis on a SDS/PAGE gel. After separation byelectrophoresis, the proteins were transferred from the gel to anitrocellulose membrane following the standard procedures. The membranewas then incubated with 10% non-fat milk in phosphate-buffered salinesupplemented with 0.1% Tween-20 (PBST) for 1 hour and then followed withan overnight incubation with a primary human AR-specific antibody(purchased from BD-PharMingen) at 4° C. After incubation, the membranewas rinsed with PBST buffer three times; 10 min each time; an alkalinephosphatase-conjugated secondary antibody was then added and incubatedfor 1 hour at room temperature. After second antibody incubation,membrane was again rinsed with PBST, and AR protein signal in themembrane was visualized by adding alkaline phosphatase substrates,bromochloroindolyl phosphate and nitro blue tetrazolium to the membrane.To assure that an equal amount of protein from each sample was analyzed,a portion of the membrane was stained with a specific antibody for ahouse keeping protein β-actin (Santa Cruz Biotechnology) and actinsignal was revealed with a second antibody as described above. Theprotein signal intensity (shown as colour band on the membrane) wasmeasured using densitometer and analysed by using NIH Image J software(NIH 1.33). The quantity of AR protein was calculated by normalizing thequantity of AR to the quantity of β-actin in each sample and data areexpressed in relative quantity.

Detection of AR Degradation Using a Cycloheximide Chasing Assay Method:

AR protein “degradation” in prostate cancer cells was measured by usingcycloheximide (a protein synthesis inhibitor) chasing assay method.Briefly, LNCaP cells were incubated with testing ASC compound at thedesignated concentrations for 24 hours. Subsequently, cycloheximide wasadded to the cells at a concentration of 15 μg/ml to block new proteinsynthesis. After incubation, cells were harvested at designated timeperiods and the resultant change in AR protein levels were analysedusing Western Blot analysis as described above.

Example 3 Preparation of Compounds and Derivatives Having(1E,6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dioneStructural Scaffold

Chemical Synthesis:

Melting points were determined using a Fisher-John melting pointapparatus without calibration. Proton Nuclear Magnetic Resonance (¹HNMR) and ¹³C NMR spectra were measured on Inova 400 spectrometers withtetramethylsilane as the internal standard. Chemical shifts werereported in δ (ppm). Mass spectra (MS) were obtained on a ShimadzuLCMS-2010. A CombiFlash chromatographic system was performed over Gracesilica gel cartridge for general separation and purification.Preparative thin layer chromatography using silica gel plates (Kieselgel60, F254, 1.00 mm) were also used for separation and purification.Precoated silica gel plates (Kieselgel 60, F254, 0.25 mm) were used forthin layer chromatography (TLC) analysis. All reagents and solvents werepurchased from Aldrich, Fisher, VWR, or other venders.

Synthesis of Compounds 1-8

Compounds 1-8 were synthesized with a general procedure as illustratedin Scheme 14. An example to make the compound 2 was described as below.To a solution of JM17 (5.0 g) in dry acetone (50 mL) was added methyliodide (2.5 nil) and K₂CO₃ (5.0 g). The reaction mixture was refluxedand stirred for 2 days with TLC monitoring. The reaction mixture wascooled down and filtered to remove inorganic powder then vacuumevaporated. The obtained crude was purified by silica gel columnchromatography eluted by hexane and EtOAc mixture to get the desiredproduct.

Compound 1, pale yellow amorphous. ESI MS m/z: 465.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.66 (d, 2H, J=15.6 Hz, H-1,7), 7.10 (dd, 2H, J=2.0, 8.4Hz, aromatic H-6′), 6.97 (d, 2H, J=2.0 Hz, aromatic H-2′), 6.81 (d, 2H,J=8.4 Hz, aromatic 14-5′), 6.63 (d, 2H, J=15.6 Hz, H-2,6), 3.87 (12H,OCH₃×4), 1.97 (d, 2H, J=6.4 Hz, CH₂—C4), 1.53 (s, 3H, CH₃—C4), 0.6-0.03(m, 5H of cyclopropane).

Compound 2, white-yellow crystal, mp 161-162° C. ESI MS m/z: 479.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, 2H, J=15.2 Hz, H-1,7), 7.09(dd, 2H, J=2.6, 8.4 Hz, aromatic H-6′), 6.96 (d, 2H, J=2.0 Hz, aromaticH-2′), 6.80 (d, 2H, J=8.4 Hz, aromatic H-5′), 6.59 (d, 2H, J=15.2 Hz,H-2,6), 3.87 (12H, OCH₃×4), 3.0-1.6 (m, 7H of cyclobutane), 1.39 (s, 3H,CH₃—C4), 1.22 (t, 2H, J=6.9 Hz, CH₂—C4).

Compound 4, pale yellow amorphous. ESI MS m/z: 493.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.64 (d, 2H, J=15.2 Hz, H-1,7), 7.09 (dd, 2H, J=2.6, 8.4Hz, aromatic H-6′), 6.96 (d, 2H, J=2.0 Hz, aromatic H-2′), 6.80 (d, 2H,J=8.4 Hz, aromatic H-5′), 6.59 (d, 2H, J=15.2 Hz, H-2,6), 3.87 (12H,OCH₃×4), 3.0-1.6 (m, 7H of cyclopentane), 1.39 (s, 3H, CH₃—C4), 1.22 (t,2H, J=6.9 Hz, CH₂—C4).

Compound 5, pale yellow crystal, mp 128-129° C. ESI MS m/z: 507.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ: 7.63 (d, 2H, J=15.6 Hz, H-1,7), 7.10(dd, 2H, J=2.6, 8.4 Hz, aromatic H-6′), 6.97 (d, 2H, J=2.0 Hz, aromaticH-2′), 6.81 (d, 2H, J=8.4 Hz, aromatic H-5′), 6.65 (d, 2H, J=15.6 Hz,H-2,6), 3.87 (12H, OCH₃×4), 1.97 (d, 2H, J=5.6 Hz, CH₂—C4), 1.65-0.85(m, 11H of cyclohexane), 1.46 (s, 3H, CH₃—C4).

Compound 6, off-white crystal, ESI MS m/z: 524.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.63 (d, 2H, J=15.6 Hz, H-1,7), 7.09 (dd, 2H, J=2.0, 8.0Hz, aromatic H-6′), 6.98 (d, 2H, J=2.0 Hz, aromatic H-2′), 6.80 (d, 2H,J=15.6 Hz, H-2,6), 6.80 (d, 2H, J=8.0 Hz, aromatic H-5′), 3.85 (12H,OCH₃×4), 3.39-3.28 (m, 4H, —N(CH₂CH₃)₂, 3.12 (s, 2H, C4-CH₂CO), 1.62 (s,3H, CH₃—C4), 1.20 (t, 3H, J=7.2 Hz, —N(CH₂CH₃)₂), 1.04 (t, 3H, J=7.2 Hz,—N(CH₂CH₃)₂.

Compound 7, off-white crystal, ESI MS m/z: 496.4 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.63 (d, 2H, J=15.6 Hz, H-1,7), 7.09 (dd, 2H, J=8.4 Hz,aromatic H-6′), 6.97 (s, 2H, aromatic H-2′), 6.81 (d, 2H, J=15.6 Hz,H-2,6), 6.80 (d, 2H, J=8.4 Hz, aromatic H-5′), 3.85 (12H, OCH₃×4), 3.17(s, 2H, C4-CH₂CO), 3.06 (s, 3H, —N(CH₃)₂), 2.88 (s, 3H, —N(CH₃)₂), 1.64(s, 3H, CH₃—C4).

Compound 8, light yellow crystal, EST MS m/z: 467.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.64 (d, 2H, J=15.6 Hz, H-1,7), 7.09 (d, 2H, J=8.4 Hz,aromatic H-6′), 6.98 (d, 2H, J=2.0 Hz, aromatic H-2′), 6.80 (d, 2H,J=8.4 Hz, aromatic H-5′), 6.63 (d, 2H, J=15.6 Hz, H-2,6), 3.86 (12H,OCH₃×4), 2.00-1.96 (m, 2H, —CH₂(CH₂)₂CH₃), 1.42 (s, 3H, CH₃—C4),1.34-1.27 (m, 2H, CH₂(CH₂)₂CH₃), 1.16-1.10 (m, 2H, —CH₂(CH₂)₂CH₃), 0.85(t, 3H, J=6.8 Hz, —CH₂(CH₂)₂CH₃).

Synthesis of Compounds 9-12

Compounds 9-12 were synthesized with a general procedure as illustratedin Scheme 15.

Chloroacetic acid (2 eq.) was dissolved in methylene chloride. To thesolution was added a solution of DCC (1 eq.) in methylene chloride. Themixture was stirred at rt for 10 min, and a solution of DMAP (0.5 eq)and an appropriate amine in methylene chloride was added slowly. Thereaction mixture was allowed to stir at rt overnight or with TLCmonitoring. The solid was filtered and the filtrate was washed withwater, 6N HCl, 6N NaOH and water. After drying over Na₂SO₄, andevaporating to remove solvent, the desired amide product was obtainedwithout further purification. Reaction of the amide (leg.) with2,4-pentanedione (1.5 eq.) in acetonitrile in the presence of DBU (leg.)at rt yielded a corresponding product 3-acetyl-4-oxopentanamide asillustrated in the Scheme 2. The resulting product (1 eq.) was thenmixed the 3,4-dimethoxybenzaldehyde (2 eq.) in the presence of B₃O₂ (0.5eq.), (BuO)₃B (2 eq.) and NH₂Bu (0.4 eq.) in DMA and the mixture wasallowed to stir at 65° C. for 3-5 h with TLC monitoring. 1% HCl aqueouswas added upon the reaction completion, and the resulting mixture wasstirred at 65° C. for 1-2 hours. The mixture was then diluted with ethylacetate and extracted with water twice or until pH˜5. The ethyl acetateextract was dried over Na2SO4, filtered and concentrated. The crude waspurified by crystallization from ethyl acetate or Combiflash columechromatograph to give the desired product, such as compound 9 or 10.Reaction of 9 or 10 by following the procedure described in the Scheme 1yielded the compounds 11 and 12.

Compound 9, light-yellow crystalline solid, ESI MS m/z: 524.5 [M+H]⁺, ¹HNMR (400 MHz, CDCl₃) δ: 7.64 (d, 2H, J=15.6 Hz, H-1,7), 7.11 (dd, 2H,J=2.0, 8.4 Hz, aromatic H-6′), 7.02 (d, 2H, J=1.6 Hz, aromatic H-2′),6.82 (d, 2H, J=8.4 Hz, aromatic H-5′), 6.76 (d, 2H, J=15.6 Hz, H-2,6),3.87 (s, 6H, OCH₃×2), 3.84 (s, 6H, OCH₃×2), 3.70-3.65 (m, 4H,morpholine-H), 3.63-3.59 (m, 4H, morpholine-H), 3.57-3.52 (m, 1H, C4-H),3.00 (d, 2H, J=6.8 Hz, C4-CH₂CO).

Compound 10, red-orange crystalline solid, ESI MS m/z: 551.6 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ: 7.68 (d, 2H, J=15.6 Hz, H-1,7), 7.43 (d, 1H,J=4.0 Hz, thiazole-H), 7.15 (dd, 2H, J=2.0, 8.4 Hz, aromatic H-6′), 7.01(d, 2H, J=2.0 Hz, aromatic H-2′), 6.90 (d, 1H, J=4.0 Hz, thiazole-H),6.83 (d, 2H, J=8.4 Hz, aromatic H-5′), 6.78 (d, 2H, J=15.6 Hz, H-2,6),3.87 (s, 6H, OCH₃×2), 3.85 (s, 6H, OCH₃×2), 2.98 (s, 2H, C4-CH₂CO).

Compound 11, light yellow crystalline solid, ESI MS m/z: 538.6 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ: 7.65 (d, 2H, J=15.2 Hz, H-1,7), 7.09 (dd, 2H,J=2.0, 8.4 Hz, aromatic H-6′), 6.98 (d, 2H, J=2.0 Hz, aromatic H-2′),6.80 (d, 2H, J=15.2 Hz, H-2,6), 6.80 (d, 2H, J=8.4 Hz, aromatic H-5′),3.87 (s, 6H, OCH₃×2), 3.82 (s, 6H, OCH₃×2), 3.68-3.60 (m, 4H,morpholine-H), 3.56-3.53 (m, 4H, morpholine-H), 3.15 (s, 2H, C4-CH₂CO),1.64 (s, 3H, CH₃—C4).

Compound 12, light yellow crystalline solid, ESI MS m/z: 551.6 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ: 7.69 (d, 2H, J=15.2 Hz, H-1,7), 7.45 (d, 1H,J=4.0 Hz, thiazole-H), 7.12 (dd, 2H, J=2.0, 8.4 Hz, aromatic H-6′), 6.99(d, 2H, J=2.0 Hz, aromatic H-2′), 6.93 (d, 1H, J=4.0 Hz, thiazole-H),6.81 (d, 2H, J=15.2 Hz, H-2,6), 6.81 (d, 2H, J=8.4 Hz, aromatic H-5′),3.87 (s, 6H, OCH₃×2), 3.85 (s, 6H, OCH₃×2), 3.46 (s, 2H, C4-CH₂CO), 1.72(s, 3H, CH₃—C4).

Synthesis of Compounds 13-19

The compounds 13-19 were synthesized with the general method asillustrated in Scheme 16. An example to make compound 14 was describedas below. To a solution of JM17 (2.2 g) in acetonitrile (20 mL) wasadded N-Fluorodibenzenesulfonimide (1.5 g). The reaction mixture wasstirred at room temperature for 1 day with TLC monitoring. The reactionmixture was vacuum evaporated and obtained crude was purified by silicagel column chromatography eluted by hexanes and EtOAc mixture to get thedesired product.

Compound 13, pale yellow crystal, mp 104-105° C. ESI MS m/z: 469.2[M+H]⁺, ¹H NMR (400 MHz, CDCl₃) δ: 7.72 (d, 2H, J=15.6 Hz, H-1,7), 7.18(dd, 2H, J=2.6, 8.4 Hz, aromatic H-6′), 7.09 (dd, 2H, J_(H-F)=2.4, 15.6Hz, H-2,6), 7.08 (d, 2H, J=2.0 Hz, aromatic H-2′), 6.84 (d, 2H, J=8.4Hz, aromatic H-5′), 3.91, 3.90 (both s, 6H each, OCH₃×4), 2.20 (dd, 2H,J=7.0, 24.4 Hz, CH₂—C4), 0.8-0.1 (m, 5H of cyclopropane).

Compound 14, pale yellow crystal, mp 98-100° C. ESI MS m/z: 483.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ: 7.70 (d, 2H, J=16 Hz, H-1,7), 7.17(dd, 2H, J=2.6, 8.4 Hz, aromatic H-6′), 7.08 (d, 2H, J=2.0 Hz, aromaticH-2′), 7.05 (dd, 2H, J_(H-F)=2.8, 16 Hz, H-2,6), 6.84 (d, 2H, J=8.4 Hz,aromatic H-5′), 3.91, 3.89 (both s, 6H each, OCH₃×4), 2.5-1.7 (m, 9H ofmethylcyclobutane).

Compound 15, pale yellow amorphous. ESI MS m/z: 497.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ: 7.70 (d, 2H, J=16 Hz, H-1,7), 7.17 (dd, 2H, J=2.6,8.4 Hz, aromatic H-6′), 7.08 (d, 2H, J=2.0 Hz, aromatic H-2′), 7.05 (dd,2H, J_(H-F)=2.8, 16 Hz, H-2,6), 6.84 (d, 2H, J=8.4 Hz, aromatic H-5′),3.91, 3.89 (both s, 6H each, OCH₃×4), 2.5-1.7 (m, 9H ofmethylcyclopentane).

Compound 16, pale yellow amorphous. ESI MS m/z: 511.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ: 7.71 (d, 2H, J=15.6 Hz, H-1,7), 7.17 (dd, 2H, J=2.0,8.4 Hz, aromatic H-6′), 7.09 (d, 2H, J=2.0 Hz, aromatic H-2′), 7.08 (dd,2H, J_(H-F)=2.0, 16 Hz, H-2,6), 6.84 (d, 2H, J=8.4 Hz, aromatic H-5′),3.91, 3.89 (both s, 6H each, OCH₃×4), 2.19 (dd, 2H, J=6.4, 24.8 Hz,CH₂—C4), 1.8-0.9 (m, 11H of cyclohexane).

Compound 17, off-white crystal, ESI MS m/z: 528.5 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.73 (d, 2H, J=15.6 Hz, H-1,7), 7.24 (dd, 2H, J=2.4, 15.6Hz, H-2,6), 7.19 (dd, 2H, J=1.6, 8.4 Hz, aromatic H-6′), 7.12 (d, 2H,J=2.0 Hz, aromatic H-2′), 6.85 (d, 2H, J=8.4 Hz, aromatic H-5′), 3.91(s, 12H, OCH₃×4), 3.48 (d, 2H, J=24.4 Hz, C4-CH₂CO), 3.40-3.29 (m, 4H,—N(CH₂CH₃)₂, 1.21 (t, 3H, J=7.2 Hz, —N(CH₂CH₃)₂), 1.10 (t, 3H, J=7.2 Hz,—N(CH₂CH₃)₂.

Compound 18, off-white crystal, ESI MS m/z: 500.4 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.71 (d, 2H, J=15.2 Hz, H-1,7), 7.20 (dd, 2H, J=2.4, 15.2Hz, H-2,6), 7.17 (d, 2H, J=8.0 Hz, aromatic H-6′), 7.11 (s, 2H, aromaticH-2′), 6.83 (d, 2H, J=8.4 Hz, aromatic H-5′), 3.89 (s, 12H, OCH₃×4),3.47 (d, 2H, J=25.2 Hz, C4-CH₂CO), 3.01 (s, 31-1, —N(CH₃)₂), 2.92 (s,3H, —N(CH₃)₂).

Compound 19, light yellow crystal, ESI MS m/z: 471.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.72 (d, 2H, J=15.6 Hz, H-1,7), 7.17 (dd, 2H, J=1.6, 8.4Hz, aromatic H-6′), 7.08 (d, 2H, J=2.0 Hz, aromatic H-2′), 7.06 (dd, 2H,J=2.8, 15.6 Hz, H-2,6), 6.84 (d, 2H, J=8.4 Hz, aromatic H-5′), 3.91 (s,6H, OCH₃×2), 3.90 (s, 6H, OCH₃×2), 2.29-2.19 (m, 2H, —CH₂(CH₂)₂CH₃),1.40-1.30 (m, 4H, CH₂(CH₂)₂CH₃), 0.88 (t, 3H, J=6.8 Hz, —CH₂(CH₂)₂CH₃).

Synthesis of Compounds 20-21

Compounds 20 and 21 were synthesized with the method as illustrated inthe Scheme 17. To a solution of Q49 or Q77 (1 eq.) in THF was added Et₃N(1.5 eq.). The mixture was cooled in an ice-bath andtrifluoromethanesulfonyl chloride (1 eq.) in THF was added slowly. Thereaction mixture was allowed to stir at (1 h) then heat to 50° C. for 5hour or with TLC monitoring. The reaction was quenched by addition ofice water and ethyl acetate. After extracting with water followed byethyl acetate, the crude was purified by Combiflash column chromatographeluting with methylene chloride and ethyl acetate to get the desiredproduct.

Compound 20, off-white crystal, ESI MS m/z: 545.5 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.73 (d, 2H, J=15.6 Hz, H-1,7), 7.15 (d, 2H, J=15.6 Hz,H-2,6), 7.15-7.13 (m, 2H, aromatic H-6′), 7.04 (br, 2H, aromatic H-2′),6.82 (d, 2H, J=8.4 Hz, aromatic H-5′), 3.88 (s, 6H, OCH₃×2), 3.82 (s,6H, OCH₃×2), 3.60 (s, 2H, C4-CH₂CO), 3.38-3.33 (m, 4H, —N(CH₂CH₃)₂, 1.22(t, 3H, J=6.8 Hz, —N(CH₂CH₃)₂), 1.08 (t, 3H, J=6.8 Hz, —N(CH₂CH₃)₂.

Compound 21, off-white crystal, ESI MS m/z: 516.4 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ: 7.69 (d, 2H, J=15.6 Hz, H-1,7), 7.18 (d, 2H, J=15.6 Hz,H-2,6), 7.14 (dd, 2H, J=3.6, 10.0 Hz, aromatic H-6′), 7.04 (d, 2H, J=2.0Hz, aromatic H-2′), 6.82 (d, 2H, J=8.4 Hz, aromatic H-5′), 3.89 (s, 6H,OCH₃×2), 3.82 (s, 6H, OCH₃×₂), 3.62 (s, 2H, C4-CH₂CO), 3.07 (s, 3H,—N(CH₃)₂), 2.92 (s, 3H, —N(CH₃)₂).

Example 4 Detecting Biological Activity of Compounds and DerivativesHaving(1E,6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dioneStructural Scaffold

The materials and methods used in this example have been described abovein this application, such as but not limited to, Example 2. The resultsof the following assays and experiments are provided in Table 2.

For AR reduction, the indicated compound induced AR protein expressionin cancer cells as assayed and determined by Western blotting at 24 or48 hr post-incubation. The dose of each compound, which induces 50%reduction of AR expression are shown.

For inhibition of tumor cell growth, in vitro, cells were growth in thepresence of testing compounds for 5 days, and the cell growth wasassayed by standard MTT assay. The dose of each compound, which induces50% growth inhibition are shown.

TABLE 2 Biological activity of Compounds and Derivatives having (1E,6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold CWR22Rv1 cells (humanprostate cancer) Reduction of AR expression Inhibition of IC₅₀ (μM)Tumor cells growth Compound 24 h 48 h IC_(50,) (μM) ASC-J9 ® 5.0 5.0 4.0 1 2.1 2.4  2 >5 >7.5  3 2.8 ND  4 3.2 2.6  5 4.0 4.6  6 1.0 1.5  7 3.52.0  8 >5 2.3  9 >7.5 ND 10 3.5 ND 11 2.2 ND 12 ND ND 13 >5 >5 14 1.53.6 15 2.5 3.2 16 3.5 4 17 >5 >7.5 18 >5 >7.5 19 >5 4.7 20 3.0 4.0 214.0 >7.5 ND = Not done.

Example 5 Improved Stability of Modified Compounds

As shown in Table 3 through Table 5, compounds Q49 and Q77, whichpossess one enol and one ketone group on the linker of two benzenerings, are chemically unstable at 37° C. in: (i) acidic condition (0.1;N (ii) in rat plasma and (iii) in human plasma. Under these conditions,for compounds Q49 and Q77, their relative concentration quickly reducedwith a period of incubation time, i.e., as early as 1 hr in acidiccondition (Q77 in Table 3). However, chemical derivatives according tothe Formula VI, where Q49 was modified to Compound 6 and Q77 wasmodified to Compound 7, the stability of these new derivatives (Compound6 and Compound 7) had unexpectedly and dramatically improved under allthree incubation conditions. As shown in Table 3 (acid condition), wherestability of Q77 was 8% at 1 hr., the stability improved to 99% inCompound 7. Also, at 24 hr where stability of Q49 was only 4%, while itsderivative Compound 6 had improved to 79%. Similar improvements instability (from 6-24 hr) were also observed in the conditions of ratplasma (Table 4) and human plasma (Table 5). These data indicate thatmodification of the compounds with an enol-ketone group to a di-ketonemoiety on the linker through chemical modification, according to FormulaVI, their chemical as well as metabolic stability has unexpectedly anddramatically improved.

TABLE 3 Relative compound concentration changes (stability) in acidiccondition Concentration change, % Time, h Q49 Compound 6 Q77 Compound 70 100  100  100  100  1 73 — 14  — 2 56 100  8 99 4 — 99 — 98 6 38 — 0 —24  4 79 0 81 48 — 56 — 58

TABLE 4 Relative compound concentration changes (stability) in ratplasma Time, hours Concentration change, % Rat plasma Q49 Compound 6 Q77Compound 7 0 100 100 100 100 1 68 98 93 101 2 54 96 88 100 6 27 93 73101 24 2 77 27 99 48 0 51 7 86

TABLE 5 Relative compound concentration changes (stability) in humanplasma Time, hours Concentration change, % Human plasma Q49 Compound 6Q77 Compound 7 0 100 100 100 100 1 90 99 88 100 2 75 97 76 99 6 41 91 4595 24 9 54 11 71 48 0 27 1 49

All publications, including patent documents and scientific articles,referred to in this application and any bibliography and attachments,are incorporated by reference in their entirety for all purposes to thesame extent as if each individual publication were individuallyincorporated by reference.

All headings are for the convenience of the reader and should not beused to limit the meaning of the text that follows the heading, unlessso specified.

What is claimed is:
 1. A pharmaceutical composition for treating asubject suffering from an androgen receptor associated medicalcondition, comprising: a compound according to formula VI:

wherein: L is a carbonyl, alkylene, —CH₂; Z is —H, —OH, a substitutedstyrenyl, an aromatic ring, a cycloalkyl, —COR₁, —CONR₁R₂, or —CX₃,wherein R₁ and R₂ are the same or different and are each —H, —CH₃, or—C_(n)H_(2n+1), (n=2-4), or a heterocyclic, or a heteroaryl, or acycloalkyl, or a cyclopentanyl alkenylene, or an alkynl, or a heteroarylmoiety, or R₁ and R₂ together to form a heterocyclic ring, or amorphorine; X is —F, —Cl, or —Br; and Y is a short alkyl(C1-3), a methyl(—CH₃), or —F, —Cl, —Br; or a compound according to formula VII:

wherein: R₁ is selected, from the group consisting of

and R₂ is selected from the group consisting of CH₃, H, F and Cl;further wherein said pharmaceutical composition treats said subjectsuffering from said androgen receptor associated medical condition. 2.The pharmaceutical composition according to claim 1, wherein saidandrogen receptor associated medical condition is an androgen receptorassociated medical condition that is induced, caused or mediated by anormal or abnormal androgen receptor.
 3. The pharmaceutical compositionaccording to claim 1, wherein said androgen receptor associated medicalcondition is inflammation.
 4. The pharmaceutical composition accordingto claim 1, wherein said androgen receptor associated medical conditionis acne.
 5. The pharmaceutical composition according to claim 1, whereinsaid androgen receptor associated medical condition is alopecia.
 6. Thepharmaceutical composition according to claim 1, wherein said androgenreceptor associated medical condition is hirsutism.
 7. Thepharmaceutical composition according to claim 1, wherein said androgenreceptor associated medical condition is a wound.
 8. The pharmaceuticalcomposition according to claim 1, wherein said androgen receptorassociated medical condition is Spinal and Bulbar Muscular Atrophy(SBMA, Kennedy's Disease).
 9. The pharmaceutical composition accordingto claim 1, wherein said androgen receptor associated medical conditionis cancer.
 10. The pharmaceutical composition according to claim 1,wherein said androgen receptor associated medical condition is prostatecancer.
 11. The pharmaceutical composition according to claim 1, whereinsaid androgen receptor associated medical condition is bladder cancer.12. The pharmaceutical composition according to claim 1, wherein saidandrogen receptor associated medical condition is liver cancer.
 13. Thepharmaceutical composition according to claim 1, wherein said androgenreceptor associated medical condition is breast cancer.
 14. Thepharmaceutical composition according to claim 1, wherein said androgenreceptor associated medical condition is pancreatic cancer.
 15. Thepharmaceutical composition according to claim 1, wherein said androgenreceptor associated medical condition is ovarian cancer.
 16. Thepharmaceutical composition according to claim 1, wherein saidpharmaceutical composition comprises a pharmaceutically acceptablecarrier.
 17. The pharmaceutical composition according to claim 1,wherein said subject is human.
 18. The pharmaceutical compositionaccording to claim 1, wherein said subject is non-human.
 19. Thepharmaceutical composition according to claim 1, wherein said subject isa patient.
 20. The pharmaceutical composition according to claim 1,wherein said androgen receptor associated medical condition is anunwanted immune response.
 21. The pharmaceutical composition accordingto claim 1, wherein said androgen receptor associated medical conditionis an immune disorder.
 22. The pharmaceutical composition according toclaim 1, wherein said pharmaceutical composition is provided in atherapeutically effective amount.
 23. A method of treating a subjectsuffering from an androgen receptor associated medical condition,comprising: a) providing a subject; and b) administering to saidpatient, a therapeutically effective amount of a compound according toclaim
 1. 24. The method of treating a subject suffering from an androgenreceptor associated medical condition according to claim 23, whereinsaid androgen receptor associated medical condition is an androgenreceptor associated medical condition that is induced, caused ormediated by a normal or abnormal androgen receptor.
 25. The method oftreating a subject suffering from an androgen receptor associatedmedical condition according to claim 23, wherein said androgen receptorassociated medical condition is inflammation.
 26. The method of treatinga subject suffering from an androgen receptor associated medicalcondition according to claim 23, wherein said androgen receptorassociated medical condition is acne.
 27. The method of treating asubject suffering from an androgen receptor associated medical conditionaccording to claim 23, wherein said androgen receptor associated medicalcondition is alopecia.
 28. The method of treating a subject sufferingfrom an androgen receptor associated medical condition according toclaim 23, wherein said androgen receptor associated medical condition ishirsutism.
 29. The method of treating a subject suffering from anandrogen receptor associated medical condition according to claim 23,wherein said androgen receptor associated medical condition is a wound.30. The method of treating a subject suffering from an androgen receptorassociated medical condition according to claim 23, wherein saidandrogen, receptor associated medical condition is Spinal and BulbarMuscular Atrophy (SBMA, Kennedy's Disease).
 31. The method of treating asubject suffering from an androgen receptor associated medical conditionaccording to claim 23, wherein said androgen receptor associated medicalcondition is cancer.
 32. The method of treating a subject suffering froman androgen receptor associated medical condition according to claim 23,wherein said androgen receptor associated medical condition is prostatecancer.
 33. The method of treating a subject suffering from an androgenreceptor associated medical condition according to claim 23, whereinsaid androgen receptor associated medical condition is bladder cancer.34. The method of treating a subject suffering from an androgen receptorassociated medical condition according to claim 23, wherein saidandrogen receptor associated medical condition is liver cancer.
 35. Thewherein said androgen receptor associated medical condition is breastcancer.
 36. The method of treating a subject suffering from an androgenreceptor associated medical condition according to claim 23, whereinsaid androgen receptor associated medical condition is pancreaticcancer.
 37. The method of treating a subject suffering from an androgenreceptor associated medical condition according to claim 23, whereinsaid androgen receptor associated medical condition is ovarian cancer.38. The method of treating a subject suffering from an androgen receptorassociated medical condition according to claim 23, wherein saidpharmaceutical composition comprises a pharmaceutically acceptablecarrier.
 39. The method of treating a subject suffering from an androgenreceptor associated medical condition according to claim 23, whereinsaid subject is human.
 40. The method of treating a subject sufferingfrom an androgen receptor associated medical condition according toclaim 23, wherein said subject is non-human.
 41. The method of treatinga subject suffering from an androgen receptor associated medicalcondition according to claim 23, wherein said subject is a patient. 42.The method of treating a subject suffering from an androgen receptorassociated medical condition according to claim 23, wherein saidandrogen receptor associated medical condition is an unwanted immuneresponse.
 43. The method of treating a subject suffering from anandrogen receptor associated medical condition according to claim 23,wherein said androgen receptor associated medical condition is an immunedisorder.
 44. The method of treating a subject suffering from anandrogen receptor associated medical condition according to claim 23,wherein said pharmaceutical composition is provided in a therapeuticallyeffective amount.